The Covid-19 pandemic has been awful for many reasons. But if there is a bright side to the past three years, it is vaccines. Development and testing has advanced at an unprecedented pace since the arrival of Covid-19, enabling technologies that might otherwise have taken another decade to undergo late-stage clinical testing, regulatory approval and manufacturing scale-up to prove their mettle in millions of people.
These advances have set the stage for further breakthroughs in the next five to 10 years that could help to combat some of the greatest scourges of humanity, from common respiratory infections to cancer.
“We were anticipating the arrival of a golden era for vaccines before the pandemic, but like during a war, technology tends to develops a lot quicker during a pandemic. I guess a silver lining has been the rapid development of different vaccine technology platforms,” said Prof Brendan Wren, a molecular biologist at the London School of Hygiene & Tropical Medicine.
Much of the excitement centres on mRNA-based vaccines, which use the same platform as the Covid-19 shots developed by Pfizer/BioNTech and Moderna.
Unlike traditional vaccines, which are manufactured in biological systems such as yeast or chicken’s eggs, mRNA vaccines are synthesised chemically, similar to most drugs. “It’s a huge advance, because it is essentially the same synthetic process every time, which means we can scale it,” said Prof Sir Andrew Pollard, the director of the Oxford Vaccines Group at the University of Oxford.
Although often sold as a new technology, companies had, in fact, been working on mRNA vaccines for about 20 years, mostly in the context of cancer. However, the pandemic provided the funding and political power to drive this technology over the finish line and prove its worth in hundreds of millions of people.
Since then, the number of trials exploring mRNA vaccines for other diseases has exploded. Last month, the National Institute of Health in the US launched early-stage trials of three experimental mRNA vaccines for HIV. BioNTech is already running trials of mRNA vaccines for malaria, shingles and influenza. Moderna is also testing mRNA vaccines against flu, plus RSV, Zika virus, cytomegalovirus (a leading cause of childhood birth defects) and Nipah virus, a potential pandemic threat. It is also planning clinical trials of an inhaled mRNA therapy for cystic fibrosis, in collaboration with Vertex Pharmaceuticals.
However, one of the most immediate applications is likely to be cancer. In December, Moderna announced preliminary results from a trial of its mRNA-based cancer vaccine in 157 people with melanoma, a skin cancer. When given alongside the existing immunotherapy drug Keytruda, it cut the risk of death or the cancer returning by 44%, compared with receiving Keytruda alone. BioNTech also plans to launch a trial of one of its cancer vaccine candidates in England later this year. Such vaccines are anticipated to become accessible to large numbers of patients by 2030.
Whereas mRNA vaccines against Covid provide our cells with the genetic instructions for making the coronavirus spike protein, mRNA-based cancer vaccines provide the instructions for making fragments of proteins (peptides) found on the surface of an individual patient’s cancer cells.
“It is much more challenging to develop an mRNA-based vaccine for cancer than it is for an infectious disease,” said Dr Anna Osborne, a senior healthcare analyst at the pharmaceutical intelligence firm Citeline. “When you think about the Covid vaccine, everyone can just be given the same vaccine. With cancer, every vaccine is different, because it has to be tailored to each individual person.
“But we do need to temper expectations, because it is still very challenging to produce these personalised vaccines.”
Melanoma also tends to be easier to stimulate an immune response against, compared with solid tumours. “It will also be interesting to see whether those results translate into other types of cancer,” Osborne said.
Cancer aside, an additional benefit of mRNA vaccines is the speed at which they can be manufactured. This rapidity makes it particularly attractive in the context of future pandemics. “We can make candidates now, faster than we can actually test them,” said Wren.
This is also true of viral vector vaccines – another relatively new technology that proved its mettle during the Covid-19 pandemic, with the Oxford/AstraZeneca vaccine. “For viral vector vaccines, you’ve probably got three months from a standing start to have your doses. If you’ve got the facility ready, then it’s about six weeks for an RNA vaccine,” said Pollard.
“If we had a flu pandemic tomorrow, it would be at least six months before we’d have vaccines at scale, because most of the production capacity is in eggs. So, if we can switch flu to some of these newer technologies, we have the potential to be much better able to respond to a pandemic.”
Also useful is the ability to tune the immune system against multiple antigens by injecting mRNAs for a number of different proteins at the same time. This already happens in the context of some variant-specific Covid vaccines.
“I believe that in this decade, we will be able to develop a multicomponent respiratory vaccine that can protect against Covid, flu and RSV [respiratory syncytial virus], and maybe even other respiratory viruses that cause tremendous hospitalisation burden and death around the world,” said Dr Paul Burton, Moderna’s chief medical officer.
Yet, achieving this could be challenging for other reasons. “With the Covid mRNA vaccines, a number of people felt a bit rough after having a vaccine, and although that doesn’t mean that they are unsafe, it could mean that people don’t really want to have that again,” said Prof Robin Shattock, who leads the Future Vaccine Manufacturing Research Hub at Imperial College London. One way to reduce these side-effects is to reduce the amount of mRNA that the vaccine contains, but the inclusion of mRNAs targeting multiple viruses could have the opposite effect.
Other vaccine technology has benefited from increased funding as a result of the pandemic. Others, such as protein nanoparticle-based vaccines, aim to trick the immune system into believing it is encountering a whole virus, by displaying multiple protein fragments from a virus – or many viruses – on nanoparticles. Dr Pamela Bjorkman, an assistant professor at the California Institute of Technology, is using this approach to create a broadly protective coronavirus vaccine, by combining protein fragments from multiple animal coronaviruses with pandemic potential.
“RNA is really good for pandemics, particularly viral pandemics, because it is quick to manufacture and get out there, but I don’t think it is going to be the solution to every vaccine need,” said Shattock. “This is partly because some vaccine targets are not proteins, but carbohydrates, and you can’t encode those in genetic material.”
It is also unclear whether mRNA-based vaccines can be tweaked or combined with other types of vaccine to trigger lifelong protective responses, as those based on whole dead viruses do. “It would be sensible not to put all one’s eggs in a single basket with a single technology,” Shattock said.
Also in the works are needle-free vaccines, designed to painlessly deliver viral antigens to immune cells in the skin through tiny microneedles attached to a small patch. In February, the Australian biotechnology company Vaxxas launched a phase 1 trial of a seasonal influenza vaccine patch. This is in addition to the needle-free Covid vaccine trial it is already running.
Vaxxas is also working on stabilising mRNA so it too could be delivered via a patch. “One of the major challenges the world faced in getting [Covid] vaccines to vulnerable populations was the need to store them at very low temperatures,” said Dr Richard Hatchett, the chief executive of the Coalition for Epidemic Preparedness and Innovations (Cepit), which is funding this research.
If mRNA can be stabilised and delivered through a patch, this would remove the need for frozen storage, and could even allow vaccines to be delivered to people’s homes for self-administration.
Meanwhile, Cepi is also investing in the development of “virus family vaccine libraries”. A key reason why Covid vaccines were developed so quickly was because scientists had already spent years studying the spike proteins from Mers (Middle East respiratory syndrome) and seasonal coronaviruses, and learning how to universally stabilise these proteins for vaccine development. Cepi is now working with vaccine developers to identify suitable antigens for viruses considered a high risk for future pandemics. The idea is to marry these to a plug-and-play vaccine platform, such as mRNA or the viral vector used in the Oxford/AstraZeneca vaccine, and conduct preliminary trials to gather safety and immunogenicity data.
“Building this package in advance allows you to really hit the ground running when a new virus emerges, because you’ve already worked on a similar virus in that family,” said Dr Melanie Saville, the executive director of vaccine research and development at Cepi.
Covid-19 has laid the groundwork for all of this, and may well usher in an era of improved global health, as well as ensuring we are better prepared for when the next pandemic strikes. “I think five to 10 years from now we’ll have all kinds of great options because people will continue to work on this at a basic research level,” said Bjorkman.
The pandemic has been bad, and for some people terrible. But surely, that is a silver lining worth being thankful for.
