Richard Bucala is extremely familiar with rejection. For the best part of five years, every funding proposal he sent out for his malaria vaccine program came back refused. Bucala, an immunology professor at Yale School of Medicine, wanted to develop a novel vaccine for malaria, a disease which killed over 400,000 in 2019 – most of them children aged under five. But despite some promising early results, no one seemed to be interested in Bucala’s vaccine.

“I’d explain to investors how malaria is the second leading cause of infectious disease deaths in the world,” says Bucala. “They’d recognise the importance of the problem, but it would end up being ‘Thank you. But no, thank you.’ So of course, that was deflating.”

Bucala’s vaccine is based on ribonucleic acid (RNA), a molecule that helps turn genetic code into proteins, but just a couple of years ago using RNA to create vaccines was practically unheard of. Then, of course, the coronavirus pandemic came along and shortly after, effective and quickly-developed RNA vaccines. Suddenly this previously niche technology was the biggest story in global healthcare. Cheaper, easier to develop, and vastly more scalable than the vaccines the world has relied on for more than half a century, they have single-handedly breathed new light into a branch of therapeutics that had been slowly dwindling over the last four decades.

Suddenly Bucala’s malaria ideas have started attracting attention from a variety of foundations. Early phase clinical trials in collaboration with the Oxford Vaccine Group, are now in the pipeline. “There’s been a definite uptick in interest,” he says. “Covid-19 will be a game changer for vaccine programs.”

Until the pandemic struck, the future of vaccine research was looking decidedly bleak. Back in 2005, American vaccinologist Paul Offit – co-inventor of the RotaTeq vaccine which has been used to safeguard children in the developing world against rotavirus – bemoaned the lacuna that vaccine development had become. He penned an editorial in the journal Health Affairs titled 'Why Are Pharmaceutical Companies Gradually Abandoning Vaccines?’

Offit pointed out that part of the problem was that while vaccines actually have better odds of making onto the market than many drugs – MIT economists have calculated that private-sector vaccines succeed 39.6 per cent of the time, compared to 16.3 per cent for antivirals and antibiotics – they require a lot of upfront investment while the potential financial returns are much smaller. While global vaccine sales totalled $54 billion (£38bn) in 2019, this was comfortably eclipsed by the top ten drugs on the market which alone generated $92 billion (£66bn) in revenue.

“Vaccines had become progressively more expensive to make,” Offit says. “In the 1960s, you could do Phase III trials with a few thousand people. But those trials got much larger, and began to cost in the hundreds of millions. The Phase III rotavirus vaccine trial had 70,000 people in it, and cost $350 million (£252m). Because you only take a vaccine once, or a few times in your life, it’s much more difficult to recoup that investment, while a chronic disease patient will be taking that drug every day.”

Coupled with the growing threat of litigious action in the case of adverse events – from the 1980s onwards, all vaccine manufacturers in the US have been required to contribute funds to the National Vaccine Injury Compensation Program – more and more companies were deciding to invest their efforts elsewhere.

“Many took the perspective, ‘Why should we develop vaccines if we’re going to have to pay these extra costs?’” says Offit. “And so, the number of measles vaccine makers dropped from six to one, the number of pertussis vaccine makers from eight to one, and overall we went from 26 vaccine producers in 1955, to 18 in 1980, and just four by 2020.”

In his 2005 letter, Offit urged politicians to take action, to ensure a steady supply of existing vaccines, and fund resources into research against future threats. He argued that governments either needed to be willing to pay more for vaccines, or enter into public-private partnerships with the pharmaceutical industry to support their development.

Offit's warnings went unheeded. Over the last fifteen years, various vaccine programs against SARS, MERS, Ebola, and Zika have all fallen through, because they were considered commercially unviable. Proposed vaccine initiatives for Zika collapsed because they were projected to make a huge loss. “Naturally the pharma industry doesn’t want to invest in unprofitable vaccines for the developing world,” says Bucala. “This is also the case for malaria, dengue, chikungunya and other diseases.”

But messenger RNA (mRNA), the pioneering technology used in the Pfizer/BioNTech and Moderna Covid-19 vaccines, has the potential to change all of this. The main reason is because it enables vaccines to be made much faster, and at a fraction of the previous production costs. Traditional vaccine technology requires vast numbers of animal cells, each infected with a weakened or dead virus, which would be grown in enormous incubators or fermenters over the course of many months. In comparison, making the strands of mRNA needed for a vaccine is a cell-free, biochemical process, which can be synthesised in the lab in a matter of minutes.

“To make the flu vaccine, you need an entire warehouse of literally millions of eggs rolling around on heated rollers,” says Michael Mulqueen, vice president of business development at eTheRNA, a Belgium-based biotech company that is developing mRNA based vaccines for malaria and HIV, as well as various forms of cancer. “Just getting that ready can take four to six weeks. In the same timeframe, you can produce all the mRNA you need.”

In addition, the relatively small quantities of mRNA are required to induce an antibody response in the recipient – one dose of the Moderna Covid-19 vaccine contains 100 micrograms of mRNA – makes large clinical trials more cost effective, giving companies more leeway for experimenting with new vaccines. Offit points out that a mere one litre of mRNA can generate 10 million doses of the Moderna vaccine.

Because mRNA vaccines are fairly easily reproducible – the way the RNA is packaged and produced stays largely the same – some liken mRNA vaccines to software. Moderna has even trademarked the name “mRNA OS”.

Along with other companies, Modern is now planning to go after infectious diseases which were previously considered unlikely targets for vaccines, including Zika, chikungunya and cytomegalovirus. Since Covid-19 brought mRNA vaccines to the forefront of the world’s attention, eTheRNA says it is now receiving two to three calls a week from potential investors Before the pandemic, it would have taken at least two months to receive the same level of interest.

“We're now seeing more companies coming back into the vaccine space,” says Ron Renaud, CEO of US-based Translate Bio, a biotech firm that is working on a range of mRNA vaccines in collaboration with French company Sanofi Pasteur. “It’s going to lead to a resurgence of interest in rarer viruses and infectious disease areas that have previously been overlooked.”

One of the factors which makes mRNA vaccines for diseases like Zika and chikungunya far more practical than ever before, is that batches can be produced in relatively small facilities. According to Bernard Sagaert, chief operational officer at eTheRNA, this could usher in an era where vaccines are directly made in the countries where they are needed most, eliminating a lot of the problems which arise from shipping and transporting such sensitive products around the globe, and making it easier for manufacturers to strike partnerships with national and regional governments across the developing world. “Messenger RNA vaccines have a much smaller footprint compared to traditional vaccines, in terms of materials needed, which allows for more decentralised manufacturing, and a lot more flexibility,” says Sagaert. “If you target a relatively rare disease, it’s now much more manageable to produce vaccines on a smaller scale.”

Next generation RNA technologies could also cut the costs of vaccine production even more in years to come. Bucala believes the true game changer will be a technology called self-amplifying RNA (saRNA), which is the basis of his malaria vaccine program. Just like mRNA vaccines, saRNA vaccines instruct the immune system to produce antibodies against the target infection, but once inside the body’s cells at the injection site, saRNA actually produces copies of itself over the course of six to eight weeks. This means you can induce the same response as an mRNA vaccine, but with a far smaller dose. In some studies, robust immune responses have been generated with just one microgram of saRNA.

So far saRNA remains at a research stage, but Bucala is hoping that clinical trials of his proposed malaria vaccine will be possible in the next couple of years. “With saRNA, you're reducing the dose required by 50, maybe 100 fold,” he says. “It makes the vaccines both technically simpler to produce and lower cost, and because you’re injecting less RNA into the body, which is inflammatory, you have fewer side effects.”

Of course, RNA platforms alone are not going to suddenly persuade the world’s pharmaceutical giants to transition to vaccines. While Pfizer is expecting to generate a reported $15 billion (£11bn) in profits from the Covid-19 vaccine it developed in partnership with BioNTech, most of the major pharma players are still primarily dedicating resources to sectors traditionally perceived as being more profitable, such as drug discovery for cardiovascular and neurological disorders. Bucala believes that the future of vaccine development will still rely heavily on the support of foundations, and government-initiated public-private partnerships, which have yielded the existing vaccines we have for malaria, Ebola and Covid-19.

However the emergence of such technologies have helped move vaccine development from an economically barren backwater of the medical world, to a sector brimming with new-found optimism.

“Most of the interest in funding new vaccine programs is coming from foundations, rather than pharma,” says Bucala. “But the success of the Covid-19 mRNA platforms has created new interest and growth in the field. People have seen that vaccine production is less expensive, everything is faster and cheaper. It’s a big opportunity for the whole field.”

• 📚 The future of medicine, AI and climate change: get WIRED books
• Canary Wharf is trying to reinvent itself
• The hunt for a drug that can stop Covid-19 infections
• How to get your new puppy ready for post-lockdown life
• Police unions on Facebook are harassing LGBTQ people
• Lewis Hamilton opens up about activism and life beyond F1
• 🔊 Subscribe to the WIRED Podcast. New episodes every Friday

This article was originally published by WIRED UK