When Tom Pooley, 21, became the first person to receive an experimental vaccine against plague as part of a medical trial last summer after tests on mice, he was inspired by the thought that his involvement could help to rid the world of one of the most brutal killers in human history.
“They made it quite clear I was the first human to receive it,” says Pooley, a radiotherapy engineering student. “They didn’t dress it up, but they made it clear it was as safe as possible. There are risks, but they are talented people: it’s a big honour to be the first.” The single-shot, based on the Chadox technology developed by the Oxford Vaccine Group and AstraZeneca, took less than five seconds to painlessly administer, he says. That night, he felt a little unwell, but he was fine within three hours; and the small trial continued apace to combat the centuries-old bacteria threat, which killed 171 in Madagascar as recently as 2017. It uses a weakened, genetically altered version of a common-cold virus from chimpanzees.
It is just one example of how scientists are increasingly looking at how Covid treatments can help to treat other diseases. Trials are expected to be developed for other similar jabs against dengue, Zika and a whole host of pathogens. Another vaccine study against Ebola is already going to human trials. As Professor Sarah Gilbert, architect of the Oxford Vaccine, has said: “We’ve got the cake and we can put a cherry on top, or we can put some pistachios on top if we want a different vaccine, we just add the last bit and then we’re ready to go.”
The Covid pandemic sparked an unprecedented drive to control a lethal disease whose outbreak led to a near global shutdown to contain its spread. Billions in public and private money were pumped into research like never before in such a short space of time. It’s not something the medical world would have chosen, but the developments of the past two years could not have happened without Covid-19 – the pathogen has served as a giant catalyst ushering in different technologies, data and research that offer insights into other diseases.
The lessons that have been learned – and the new norms that have solidified – will change medical science forever. The world now sits on the verge of a number of potentially significant breakthroughs, mostly thanks to the growing research into hi-tech vaccines, which could benefit patients with cancer and a whole raft of infectious diseases. Meanwhile, new studies into long Covid could shine a light into blood clotting, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other conditions associated with the stubborn virus. Obesity and vitamin levels are under the microscope; while digitisation and increased cross-border collaboration could soon reap rewards.
“Covid has stimulated the rapid translation of previous knowledge into practice,” says Independent Sage member and UCL professor of virology, Deenan Pillay. “Developing science takes many years and needs an opportunity to be implemented. Covid has provided an easier regulatory environment, with fast-tracked trials, so vaccine developments, for example, have been really quick.” Until Covid it could take a decade or more for a new vaccine or drug to go through all the development and regulatory stages, he adds, but now they have been rolled out within 12 months of first description of the disease. “Our expectations are now for a much more rapid translation and implementation of scientific advances,” says Pillay. “The caveat to this is the continuing need for equity of access to these advances, which is yet to be seen with Covid vaccines and drugs.”
Just five years ago, there was widespread hesitation to invest in experimental drugs that use synthetic molecules to guide human cells into making specific proteins that can defend against diseases. No product based on mRNA (which stands for messenger ribonucleic acid, and provides recipes to create proteins) technology had ever been approved, but within two years, the rapid development and success of Pfizer/BioNTech and Moderna’s jabs against Covid were a gamechanger.
The US big pharma giant Pfizer was already working with German start-up BioNTech, which has significant mRNA expertise, on a flu jab before the emergence of Covid. Then focus shifted to developing a vaccine for the pandemic and the pressing need for a treatment to be created accelerated steps into the next frontier – research into treatments based on RNA, a strand of nucleic acid that transfers the instructions needed to make proteins.
“It’s been an unforeseen benefit of the pandemic because RNA and mRNA vaccine technology has been researched for at least 10 years,” says Richard Bucala, the Yale school of medicine chief of rheumatology, allergy and immunology. “It wasn’t until the pandemic that RNA was really heavily invested in,” he adds. “Vaccine development is empiric: it’s very difficult to figure out if it’s going to work. It’s extremely risky. No one really wants to be involved in research and development. You don’t realise it’s a failure until you’re tens of millions into a trial. But the fortuitous success of RNA tech changed all of that.”
Relative public acceptance of an unusual hi-tech approach has also been key, and approval by a diverse range of regulatory bodies has given both investors and industry confidence. This could open the floodgates to further approvals if the new jabs impress in trials that are being prepared for humans.
Already they have their sights set on another killer disease, malaria, which is estimated to have killed almost half of all people since the Stone Age. It remained a leading cause of global infectious disease death last year: more than 600,000 people, usually young children, died from it.
Bucala’s team, in partnership with pharmaceutical company Novartis, succeeded in developing a “self-amplifying” RNA (also known as saRNA) jab for it. The technology stems from a successful RNA malaria vaccine for mice developed at Yale and is in advanced preclinical testing. It could be tested for the first time in humans within two years.
“You can potentially protect against a range of tropical diseases using self-amplifying RNA, which targets a parasite-encoded MIF protein that kills memory cells,” he says. “The self-amplification advancement will create the next generation in RNA vaccines, permitting much lower dosing and the generation of critically needed memory T-cell responses. All of this will unfold in the next five to 10 years.”
Or even earlier: at the start of February, Moderna began their trial for an HIV vaccine that relies on the same mRNA technology as the Covid jab. If they’re successful, a one-off jab will offer lifetime protection. Now this technology is being studied to see if it could help control largely treatment-resistant conditions, such as rabies, Zika, and cancer of the colon, skin, breast and other parts of the body.
Professor David Diemert, an immunologist at George Washington University, says: “The Covid pandemic really demonstrated the success of mRNA vaccines. And so the path from discussing its application for HIV to a Phase I clinical trial happened at an accelerated pace.” Dr Jeffrey Bethony, professor of microbiology, immunology and tropical medicine at George Washington School of Medicine and Health Sciences adds, “This vaccine primes the immune response against HIV by stimulating cells in the lymph node. This procedure is not just unique to Phase I trials; it’s unique for vaccines. It’s very novel.” Moderna alone is developing trials for at least another 30 mRNA-based treatments in six different areas of medicine.
Meanwhile, there has been more focus on how to tackle obesity since it has emerged as a leading factor related to Covid – 78% of US patients hospitalised between March and December 2020 were overweight. In June, the first obesity medication approved by the US Food and Drugs Administration since 2014 hit the market. Semaglutide, also known as Wegovy, could be up to twice as effective as previous weight-loss medications after a study of nearly 2,000 patients saw participants lose on average 15% of their body weight.
The synthetic version of a hormone that reduces appetite was already used in much lower doses to treat type 2 diabetes, but amid growing evidence that substantial weight loss reduces Covid severity, it was greenlighted by regulators. The availability of a drug that can improve both blood glucose and body weight could have far-reaching effects for public health beyond the context of Covid, especially for people who have remained overweight despite their best efforts.
Covid has also shone a light on the potential benefits of vitamin D. In Norway, Finland and Iceland, where there’s an emphasis on maintaining healthy levels of the vitamin, persistently low Covid mortality rates have been observed compared to other northern-hemisphere countries with less of a focus on the sunshine nutrient. Amid the ongoing search to ascertain exactly what makes some people more vulnerable to Covid than others, focus on vitamin D earlier this year led to the publication of a paper in a Lancet journal co-authored by dozens of experts, which suggested deficiencies could be a root issue in the development of many diseases
“For participants with vitamin D deficiency, genetic analyses provided strong evidence for an inverse association with all-cause mortality,” it said, calling for wider trials and a fresh look at disease prevention strategies. “There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality… There are also potential mechanisms implicating vitamin D for cancer.”
Digital health has also come to the fore as a result of pandemic responses. “Use of smartphone applications and the public understanding of data and knowledge of disease prevalence are now widespread,” says Pillay. “People are increasingly accustomed to getting clinical advice at distance, through virtual consultations, while other information collected on apps is sent to medical professionals.” Home testing is also a significant advance, as it allows people to effectively self-diagnose and thus be able to limit their exposure to others. This has come alongside rapid clinical evaluation. “Covid has provided a vision for how best to apply science to health problems in the future,” he says.
And as more in-depth research into long Covid is starting to emerge, it is throwing more light on other long-term conditions, such as ME/CFS. The crucial link here could be microclotting, an area Resia Pretorius, head of the physiological sciences department at Stellenbosch University, South Africa, has long been exploring, but the need for further understanding has become even more pressing due to Covid. The model under scrutiny proposes that small clots in blood capillaries preventing oxygen from reaching tissues may cause long-Covid symptoms.
Pretorius is now leading a study investigating this further, to understand whether microclotting could go some way to unravelling the enigma of long Covid after research in her lab detected significant formations among patients. The preliminary results of her initial research suggested that anti-clotting treatments could help ease long Covid.
“There might be a point of no return for many ME/CFS patients – this might also be the case for long Covid, if you don’t treat early in the disease onset,” says Pretorius, “then the body can become overwhelmed by inflammatory molecules that may cause significant damage. We suspect the reasons why people develop long Covid from a viral infection could be similar to why individuals develop ME/CFS.”
Pretorius, among many other scientists, has been impressed by the increasing degree of academic and research collaboration – with Covid uniting people from across the globe in a common goal that could endure. “Thank goodness, there’s a lot of like-minded researchers who have joined the endeavours from a variety of big research institutions all over the world,” she says.
If there’s one area of optimism, it is this move towards scientific collaboration and the impressive advances that have emerged in such a relatively short space of time. “It’s been such a horrific time for so many people”, agrees David Braun, an oncologist and scientist focusing on cancer immunotherapies at the Yale Cancer Centre in New Haven, whose team is working to transfer the RNA technology to a cancer jab. “I hope that some of the scientific advances made during this period might help us to treat other diseases, so that at least there can be one glimmer of hope that comes out of this tremendously difficult situation.”
