Novel Technologies Could Make Coronavirus Vaccines More Stable for Worldwide Shipping
Ssendi Bosco has long known to fear the rainy season. As deputy health officer of Mubende District, a region in Central Uganda, she is only too aware of the threat that heavy storms can pose to her area's fragile healthcare facilities.
In early October, persistent rain overwhelmed the power generator that supplies electricity to most of the region, causing a blackout for three weeks. The result was that most of Mubende's vaccine supplies against diseases such as tuberculosis, diphtheria, and polio went to waste. "The vaccines need to be constantly refrigerated, so the generator failing means that most of them are now unusable," she says.
This week, the global fight against the coronavirus pandemic received a major boost when Pfizer and their German partner BioNTech released interim results showing that their vaccine has proved more than 90 percent effective at preventing participants in their clinical trial from getting COVID-19.
But while Pfizer has already signed deals to supply the vaccine to the U.S., U.K., Canada, Japan and the European Union, Mubende's recent plight provides an indication of the challenges that distributors will face when attempting to ship a coronavirus vaccine around the globe, particularly to low-income nations.
Experts have estimated that somewhere between 12 billion and 15 billion doses will be needed to immunize the world's population against COVID-19, a staggering scale, and one that has never been attempted before. "The logistics of distributing COVID-19 vaccines have been described as one of the biggest challenges in the history of mankind," says Göran Conradson, managing director of Swedish vaccine manufacturer Ziccum.
But even these estimates do not take into account the potential for vaccine spoilage. Every year, the World Health Organization estimates that over half of the world's vaccines end up being wasted. This happens because vaccines are fragile products. From the moment they are made, to the moment they are administered, they have to be kept within a tightly controlled temperature range. Throughout the entire supply chain – transportation to an airport, the flight to another country, unloaded, distribution via trucks to healthcare facilities, and storage – they must be refrigerated at all times. This is known as the cold chain, and one tiny slip along the way means the vaccines are ruined.
"It's a chain, and any chain is only as strong as its weakest link," says Asel Sartbaeva, a chemist working on vaccine technologies at the University of Bath in the U.K.
For COVID-19, the challenge is even greater because some of the leading vaccine candidates need to be kept at ultracold temperatures. Pfizer's vaccine, for example, must be kept at -70 degrees Celsius, the kind of freezer capabilities rarely found outsides of specialized laboratories. Transporting such a vaccine across North America and Europe will be difficult enough, but supplying it to some of the world's poorest nations in Asia, Africa and South America -- where only 10 percent of healthcare facilities have reliable electricity -- might appear virtually impossible.
But technology may be able to come to the rescue.
Making Vaccines Less Fragile
Just as the world's pharmaceutical companies have been racing against the clock to develop viable COVID-19 vaccine candidates, scientists around the globe have been hastily developing new technologies to try and make vaccines less fragile. Some approaches involve various chemicals that can be added to the vaccine to make them far more resilient to temperature fluctuations during transit, while others focus on insulated storage units that can maintain the vaccine at a certain temperature even if there is a power outage.
Some of these concepts have already been considered for several years, but before COVID-19 there was less of a commercial incentive to bring them to market. "We never felt that there is a need for an investment in this area," explains Sam Kosari, a pharmacist at the University of Canberra, who researches the vaccine cold chain. "Some technologies were developed then to assist with vaccine transport in Africa during Ebola, but since that outbreak was contained, there hasn't been any serious initiative or reward to develop this technology further."
In her laboratory at the University of Bath, Sartbaeva is using silica - the main constituent of sand – to encase the molecular components within a vaccine. Conventional vaccines typically contain protein targets from the virus, which the immune system learns to recognize. However, when they are exposed to temperature changes, these protein structures degrade, and lose their shape, making the vaccine useless. Sartbaeva compares this to how an egg changes its shape and consistency when it is boiled.
When silica is added to a vaccine, it molds to each protein, forming little protective cages around them, and thus preventing them from being affected by temperature changes. "The whole idea is that if we can create a shell around each protein, we can protect it from physically unravelling which is what causes the deactivation of the vaccine," she says.
Other scientists are exploring similar methods of making vaccines more resilient. Researchers at the Jenner Institute at the University of Oxford recently conducted a clinical trial in which they added carbohydrates to a dengue vaccine, to assess whether it became easier to transport.
Both research groups are now hoping to collaborate with the COVID-19 vaccine candidates being developed by AstraZeneca and Imperial College, assuming they become available in 2021.
"It's good we're all working on this big problem, as different methods could work better for different types of COVID-19 vaccines," says Sartbaeva. "I think it will be needed."
Next-Generation Vaccine Technology
While these different technologies could be utilized to try and protect the first wave of COVID-19 vaccines, efforts are also underway to develop completely new methods of vaccination. Much of this research is still in its earliest stages, but it could yield a second generation of COVID-19 vaccine candidates in 2022 and beyond.
"After the first round of mass vaccination, we could well observe regional outbreaks of the disease appearing from time to time in the coming years," says Kosari. "This is the time where new types of vaccines could be helpful."
One novel method being explored by Ziccum and others is dry powder vaccines. The idea is to spray dry the final vaccine into a powder form, where it is more easily preserved and does not require any special cooling while being transported or stored. People then receive the vaccine by inhaling it, rather than having it injected into their bloodstream.
Conradson explains that the concept of dry powder vaccines works on the same principle as dried food products. Because there is no water involved, the vaccine's components are far less affected by temperature changes. "It is actually the water that leads to the destruction of potency of a vaccine when it gets heated," he says. "We're looking to develop a dry powder vaccine for COVID-19 but this will be a second-generation vaccine. At the moment there are more than 200 first-generation candidates, all of which are using conventional technologies due to the timeframe pressures, which I think was the correct decision."
Dry powder COVID-19 vaccines could also be combined with microneedle patches, to allow people to self-administer the vaccine themselves in their own home. Microneedles are miniature needles – measured in millionths of a meter – which are designed to deliver medicines through the skin with minimal pain. So far, they have been used mainly in cosmetic products, but many scientists are working to use them to deliver drugs or vaccines.
At Georgia Institute of Technology in Atlanta, Mark Prausnitz is leading a couple of projects looking at incorporating COVID-19 vaccines into microneedle patches with the hope of running some early-stage clinical trials over the next couple of years. "The advantage is that they maintain the vaccine in a stable, dry state until it dissolves in the skin," he explains.
Prausnitz and others believe that once the first generation of COVID-19 vaccines become available, biotech and pharmaceutical companies will show more interest in adapting their products so they can be used in a dried form or with a microneedle patch. "There is so much pressure to get the COVID vaccine out that right now, vaccine developers are not interested in incorporating a novel delivery method," he says. "That will have to come later, once the pressure is lessened."
The Struggle of Low-Income Nations
For low-income nations, time will only tell whether technological advancements can enable them to access the first wave of licensed COVID-19 vaccines. But reports already suggest that they are in danger of becoming an afterthought in the race to procure vaccine supplies.
While initiatives such as COVAX are attempting to make sure that vaccine access is equitable, high and middle-income countries have already inked deals to secure 3.8 billion doses, with options for another 5 billion. One particularly sobering study by the Duke Global Health Innovation Center has suggested that such hoarding means many low-income nations may not receive a vaccine until 2024.
For Bosco and the residents of Mubende District in Uganda, all they can do is wait. In the meantime, there is a more pressing problem: fixing their generators. "We hope that we can receive a vaccine," she says. "But the biggest problem will be finding ways to safely store it. Right now we cannot keep any medicines or vaccines in the conditions they need, because we don't have the funds to repair our power generators."
In May 2022, Californian biotech Ultima Genomics announced that its UG 100 platform was capable of sequencing an entire human genome for just $100, a landmark moment in the history of the field. The announcement was particularly remarkable because few had previously heard of the company, a relative unknown in an industry long dominated by global giant Illumina which controls about 80 percent of the world’s sequencing market.
Ultima’s secret was to completely revamp many technical aspects of the way Illumina have traditionally deciphered DNA. The process usually involves first splitting the double helix DNA structure into single strands, then breaking these strands into short fragments which are laid out on a glass surface called a flow cell. When this flow cell is loaded into the sequencing machine, color-coded tags are attached to each individual base letter. A laser scans the bases individually while a camera simultaneously records the color associated with them, a process which is repeated until every single fragment has been sequenced.
Instead, Ultima has found a series of shortcuts to slash the cost and boost efficiency. “Ultima Genomics has developed a fundamentally new sequencing architecture designed to scale beyond conventional approaches,” says Josh Lauer, Ultima’s chief commercial officer.
This ‘new architecture’ is a series of subtle but highly impactful tweaks to the sequencing process ranging from replacing the costly flow cell with a silicon wafer which is both cheaper and allows more DNA to be read at once, to utilizing machine learning to convert optical data into usable information.
To put $100 genome in perspective, back in 2012 the cost of sequencing a single genome was around $10,000, a price tag which dropped to $1,000 a few years later. Before Ultima’s announcement, the cost of sequencing an individual genome was around $600.
Several studies have found that nearly 12 percent of healthy people who have their genome sequenced, then discover they have a variant pointing to a heightened risk of developing a disease that can be monitored, treated or prevented.
While Ultima’s new machine is not widely available yet, Illumina’s response has been rapid. In September 2022, the company unveiled the NovaSeq X series, which it describes as its fastest most cost-efficient sequencing platform yet, capable of sequencing genomes at $200, with further price cuts likely to follow.
But what will the rapidly tumbling cost of sequencing actually mean for medicine? “Well to start with, obviously it’s going to mean more people getting their genome sequenced,” says Michael Snyder, professor of genetics at Stanford University. “It'll be a lot more accessible to people.”
At the moment sequencing is mainly limited to certain cancer patients where it is used to inform treatment options, and individuals with undiagnosed illnesses. In the past, initiatives such as SeqFirst have attempted further widen access to genome sequencing based on growing amounts of research illustrating the potential benefits of the technology in healthcare. Several studies have found that nearly 12 percent of healthy people who have their genome sequenced, then discover they have a variant pointing to a heightened risk of developing a disease that can be monitored, treated or prevented.
“While whole genome sequencing is not yet widely used in the U.S., it has started to come into pediatric critical care settings such as newborn intensive care units,” says Professor Michael Bamshad, who heads the genetic medicine division in the University of Washington’s pediatrics department. “It is also being used more often in outpatient clinical genetics services, particularly when conventional testing fails to identify explanatory variants.”
But the cost of sequencing itself is only one part of the price tag. The subsequent clinical interpretation and genetic counselling services often come to several thousand dollars, a cost which insurers are not always willing to pay.
As a result, while Bamshad and others hope that the arrival of the $100 genome will create new opportunities to use genetic testing in innovative ways, the most immediate benefits are likely to come in the realm of research.
Bigger Data
There are numerous ways in which cheaper sequencing is likely to advance scientific research, for example the ability to collect data on much larger patient groups. This will be a major boon to scientists working on complex heterogeneous diseases such as schizophrenia or depression where there are many genes involved which all exert subtle effects, as well as substantial variance across the patient population. Bigger studies could help scientists identify subgroups of patients where the disease appears to be driven by similar gene variants, who can then be more precisely targeted with specific drugs.
If insurers can figure out the economics, Snyder even foresees a future where at a certain age, all of us can qualify for annual sequencing of our blood cells to search for early signs of cancer or the potential onset of other diseases like type 2 diabetes.
David Curtis, a genetics professor at University College London, says that scientists studying these illnesses have previously been forced to rely on genome-wide association studies which are limited because they only identify common gene variants. “We might see a significant increase in the number of large association studies using sequence data,” he says. “It would be far preferable to use this because it provides information about rare, potentially functional variants.”
Cheaper sequencing will also aid researchers working on diseases which have traditionally been underfunded. Bamshad cites cystic fibrosis, a condition which affects around 40,000 children and adults in the U.S., as one particularly pertinent example.
“Funds for gene discovery for rare diseases are very limited,” he says. “We’re one of three sites that did whole genome sequencing on 5,500 people with cystic fibrosis, but our statistical power is limited. A $100 genome would make it much more feasible to sequence everyone in the U.S. with cystic fibrosis and make it more likely that we discover novel risk factors and pathways influencing clinical outcomes.”
For progressive diseases that are more common like cancer and type 2 diabetes, as well as neurodegenerative conditions like multiple sclerosis and ALS, geneticists will be able to go even further and afford to sequence individual tumor cells or neurons at different time points. This will enable them to analyze how individual DNA modifications like methylation, change as the disease develops.
In the case of cancer, this could help scientists understand how tumors evolve to evade treatments. Within in a clinical setting, the ability to sequence not just one, but many different cells across a patient’s tumor could point to the combination of treatments which offer the best chance of eradicating the entire cancer.
“What happens at the moment with a solid tumor is you treat with one drug, and maybe 80 percent of that tumor is susceptible to that drug,” says Neil Ward, vice president and general manager in the EMEA region for genomics company PacBio. “But the other 20 percent of the tumor has already got mutations that make it resistant, which is probably why a lot of modern therapies extend life for sadly only a matter of months rather than curing, because they treat a big percentage of the tumor, but not the whole thing. So going forwards, I think that we will see genomics play a huge role in cancer treatments, through using multiple modalities to treat someone's cancer.”
If insurers can figure out the economics, Snyder even foresees a future where at a certain age, all of us can qualify for annual sequencing of our blood cells to search for early signs of cancer or the potential onset of other diseases like type 2 diabetes.
“There are companies already working on looking for cancer signatures in methylated DNA,” he says. “If it was determined that you had early stage cancer, pre-symptomatically, that could then be validated with targeted MRI, followed by surgery or chemotherapy. It makes a big difference catching cancer early. If there were signs of type 2 diabetes, you could start taking steps to mitigate your glucose rise, and possibly prevent it or at least delay the onset.”
This would already revolutionize the way we seek to prevent a whole range of illnesses, but others feel that the $100 genome could also usher in even more powerful and controversial preventative medicine schemes.
Newborn screening
In the eyes of Kári Stefánsson, the Icelandic neurologist who been a visionary for so many advances in the field of human genetics over the last 25 years, the falling cost of sequencing means it will be feasible to sequence the genomes of every baby born.
“We have recently done an analysis of genomes in Iceland and the UK Biobank, and in 4 percent of people you find mutations that lead to serious disease, that can be prevented or dealt with,” says Stefansson, CEO of deCODE genetics, a subsidiary of the pharmaceutical company Amgen. “This could transform our healthcare systems.”
As well as identifying newborns with rare diseases, this kind of genomic information could be used to compute a person’s risk score for developing chronic illnesses later in life. If for example, they have a higher than average risk of colon or breast cancer, they could be pre-emptively scheduled for annual colonoscopies or mammograms as soon as they hit adulthood.
To a limited extent, this is already happening. In the UK, Genomics England has launched the Newborn Genomes Programme, which plans to undertake whole-genome sequencing of up to 200,000 newborn babies, with the aim of enabling the early identification of rare genetic diseases.
"I have not had my own genome sequenced and I would not have wanted my parents to have agreed to this," Curtis says. "I don’t see that sequencing children for the sake of some vague, ill-defined benefits could ever be justifiable.”
However, some scientists feel that it is tricky to justify sequencing the genomes of apparently healthy babies, given the data privacy issues involved. They point out that we still know too little about the links which can be drawn between genetic information at birth, and risk of chronic illness later in life.
“I think there are very difficult ethical issues involved in sequencing children if there are no clear and immediate clinical benefits,” says Curtis. “They cannot consent to this process. I have not had my own genome sequenced and I would not have wanted my parents to have agreed to this. I don’t see that sequencing children for the sake of some vague, ill-defined benefits could ever be justifiable.”
Curtis points out that there are many inherent risks about this data being available. It may fall into the hands of insurance companies, and it could even be used by governments for surveillance purposes.
“Genetic sequence data is very useful indeed for forensic purposes. Its full potential has yet to be realized but identifying rare variants could provide a quick and easy way to find relatives of a perpetrator,” he says. “If large numbers of people had been sequenced in a healthcare system then it could be difficult for a future government to resist the temptation to use this as a resource to investigate serious crimes.”
While sequencing becoming more widely available will present difficult ethical and moral challenges, it will offer many benefits for society as a whole. Cheaper sequencing will help boost the diversity of genomic datasets which have traditionally been skewed towards individuals of white, European descent, meaning that much of the actionable medical information which has come out of these studies is not relevant to people of other ethnicities.
Ward predicts that in the coming years, the growing amount of genetic information will ultimately change the outcomes for many with rare, previously incurable illnesses.
“If you're the parent of a child that has a susceptible or a suspected rare genetic disease, their genome will get sequenced, and while sadly that doesn’t always lead to treatments, it’s building up a knowledge base so companies can spring up and target that niche of a disease,” he says. “As a result there’s a whole tidal wave of new therapies that are going to come to market over the next five years, as the genetic tools we have, mature and evolve.”
This article was first published by Leaps.org in October 2022.
The livestock trucks arrived all night. One after the other they backed up to the wood chute leading to a dusty corral and loosed their cargo — 580 head of cattle by the time the last truck pulled away at 3pm the next afternoon. Dan Probert, astride his horse, guided the cows to paddocks of pristine grassland stretching alongside the snow-peaked Wallowa Mountains. They’d spend the summer here grazing bunchgrass and clovers and biscuitroot. The scuffle of their hooves and nibbles of their teeth would mimic the elk, antelope and bison that are thought to have historically roamed this portion of northeastern Oregon’s Zumwalt Prairie, helping grasses grow and restoring health to the soil.
The cows weren’t Probert’s, although the fifth-generation rancher and one other member of the Carman Ranch Direct grass-fed beef collective also raise their own herds here for part of every year. But in spring, when the prairie is in bloom, Probert receives cattle from several other ranchers. As the grasses wither in October, the cows move on to graze fertile pastures throughout the Columbia Basin, which stretches across several Pacific Northwest states; some overwinter on a vegetable farm in central Washington, feeding on corn leaves and pea vines left behind after harvest.
Sharing land and other resources among farmers isn’t new. But research shows it may be increasingly relevant in a time of climatic upheaval, potentially influencing “farmers to adopt environmentally friendly practices and agricultural innovation,” according to a 2021 paper in the Journal of Economic Surveys. Farmers might share knowledge about reducing pesticide use, says Heather Frambach, a supply chain consultant who works with farmers in California and elsewhere. As a group they may better qualify for grants to monitor soil and water quality.
Most research around such practices applies to cooperatives, whose owner-members equally share governance and profits. But a collective like Carman Ranch’s — spearheaded by fourth-generation rancher Cory Carman, who purchases beef from eight other ranchers to sell under one “regeneratively” certified brand — shows when producers band together, they can achieve eco-benefits that would be elusive if they worked alone.
Vitamins and minerals in soil pass into plants through their roots, then into cattle as they graze, then back around as the cows walk around pooping.
Carman knows from experience. Taking over her family's land in 2003, she started selling grass-fed beef “because I really wanted to figure out how to not participate in the feedlot world, to have a healthier product. I didn't know how we were going to survive,” she says. Part of her land sits on a degraded portion of Zumwalt Prairie replete with invasive grasses; working to restore it, she thought, “What good does it do to kill myself trying to make this ranch more functional? If you want to make a difference, change has to be more than single entrepreneurs on single pieces of land. It has to happen at a community level.” The seeds of her collective were sown.
Raising 100 percent grass-fed beef requires land that’s got something for cows to graze in every season — which most collective members can’t access individually. So, they move cattle around their various parcels. It’s practical, but it also restores nutrient flows “to the way they used to move, from lowlands and canyons during the winter to higher-up places as the weather gets hot,” Carman says. Meaning, vitamins and minerals in soil pass into plants through their roots, then into cattle as they graze, then back around as the cows walk around pooping.
Cory Carman sells grass-fed beef, which requires land that’s got something for cows to graze in every season.
Courtesy Cory Carman
Each collective member has individual ecological goals: Carman brought in pigs to root out invasive grasses and help natives flourish. Probert also heads a more conventional grain-finished beef collective with 100 members, and their combined 6.5 million ranchland acres were eligible for a grant supporting climate-friendly practices, which compels them to improve soil and water health and biodiversity and make their product “as environmentally friendly as possible,” Probert says. The Washington veg farmer reduced tilling and pesticide use thanks to the ecoservices of visiting cows. Similarly, a conventional hay farmer near Carman has reduced his reliance on fertilizer by letting cattle graze the cover crops he plants on 80 acres.
Additionally, the collective must meet the regenerative standards promised on their label — another way in which they work together to achieve ecological goals. Says David LeZaks, formerly a senior fellow at finance-focused ecology nonprofit Croatan Institute, it’s hard for individual farmers to access monetary assistance. “But it's easier to get financing flowing when you increase the scale with cooperatives or collectives,” he says. “This supports producers in ways that can lead to better outcomes on the landscape.”
New, smaller scale farmers might gain the most from collective and cooperative models.
For example, it can help them minimize waste by using more of an animal, something our frugal ancestors excelled at. Small-scale beef producers normally throw out hides; Thousand Hills’ 50 regenerative beef producers together have enough to sell to Timberland to make carbon-neutral leather. In another example, working collectively resulted in the support of more diverse farms: Meadowlark Community Mill in Wisconsin went from working with one wheat grower, to sourcing from several organic wheat growers marketing flour under one premium brand.
Another example shows how these collaborations can foster greater equity, among other benefits: The Federation of Southern Cooperatives has a mission to support Black farmers as they build community health. It owns several hundred forest acres in Alabama, where it teaches members to steward their own forest land and use it to grow food — one member coop raises goats to graze forest debris and produce milk. Adding the combined acres of member forest land to the Federation’s, the group qualified for a federal conservation grant that will keep this resource available for food production, and community environmental and mental health benefits. “That's the value-add of the collective land-owner structure,” says Dãnia Davy, director of land retention and advocacy.
New, smaller scale farmers might gain the most from collective and cooperative models, says Jordan Treakle, national program coordinator of the National Family Farm Coalition (NFFC). Many of them enter farming specifically to raise healthy food in healthy ways — with organic production, or livestock for soil fertility. With land, equipment and labor prohibitively expensive, farming collectively allows shared costs and risk that buy farmers the time necessary to “build soil fertility and become competitive” in the marketplace, Treakle says. Just keeping them in business is an eco-win; when small farms fail, they tend to get sold for development or absorbed into less-diversified operations, so the effects of their success can “reverberate through the entire local economy.”
Frambach, the supply chain consultant, has been experimenting with what she calls “collaborative crop planning,” where she helps farmers strategize what they’ll plant as a group. “A lot of them grow based on what they hear their neighbor is going to do, and that causes really poor outcomes,” she says. “Nobody replanted cauliflower after the [atmospheric rivers in California] this year and now there's a huge shortage of cauliflower.” A group plan can avoid the under-planting that causes farmers to lose out on revenue.
It helps avoid overplanted crops, too, which small farmers might have to plow under or compost. Larger farmers, conversely, can sell surplus produce into the upcycling market — to Matriark Foods, for example, which turns it into value-add products like pasta sauce for companies like Sysco that supply institutional kitchens at colleges and hospitals. Frambach and Anna Hammond, Matriark’s CEO, want to collectivize smaller farmers so that they can sell to the likes of Matriark and “not lose an incredible amount of income,” Hammond says.
Ultimately, farming is fraught with challenges and even collectivizing doesn’t guarantee that farms will stay in business. But with agriculture accounting for almost 30 percent of greenhouse gas emissions globally, there's an “urgent” need to shift farming practices to more environmentally sustainable models, as well as a “demand in the marketplace for it,” says NFFC’s Treakle. “The growth of cooperative and collective farming can be a huge, huge boon for the ecological integrity of the system.”