The COVID-19 pandemic has caused profound disruption in many industries, most of it negative. But in the pharmaceutical industry, a bright spot shines.

“I think we are in this new golden age of vaccinology,” says Penny Heaton, chief executive officer of the Bill & Melinda Gates Medical Research Institute.

Experts say the potential of using our body’s code to teach it how to treat illness, as mRNA vaccines from Pfizer/BioNTech and Moderna do for COVID-19, goes far beyond the current pandemic. Some even go so far as to say that RNA and DNA treatments will transform our relationship with disease. What this adds up to is a wave of investment and exploration in the newly proven technology—and a surge of interest in the vaccine market overall.

“People have started to really think about the economics of the vaccine business, and how an early-mover advantage can lead to a dominant long-term market position for a vaccine manufacturer,” says analyst Geoffrey Porges of SVB Leerink.

The prospects

In the search for effective COVID-19 vaccines, developers around the world tried a wide spread of vaccine technologies. The result is a diversity of vaccines approved globally that provoke varying levels of immunity.

A few, including now-household names Pfizer/BioNTech and Moderna, turned to a technology that had never been used in public but had more than 25 years of research and some clinical trials to back it up: synthetically produced messenger RNA. The standout immunity produced by the two successful mRNA vaccines rocketed their makers to (in Pfizer’s case, even greater) prominence.

It also provided stark proof of concept that mRNA vaccines could be a powerful tool against disease. “The promise that a nucleic acid vaccine gives is that it can be made so rapidly,” says John Nelson, General Electric’s lead researcher on a related project for DNA vaccines funded through the Defense Advanced Research Projects Agency (DARPA).

Unlike other vaccine types, producing RNA and DNA vaccines is a matter of assembling nucleic acids and packaging the fragile genetic material in such a way as to protect it until it can make it into a cell. In the case of current vaccines, that package is a tiny particle of fat. But other technologies can be used, says Nelson.

This process means the vaccines are quick to make, compared to other kinds of vaccines that use components that have to be grown, and they can be modified with relative ease. mRNA technology, for instance, was first developed for use in personalized cancer medicine, although it has yet to be implemented at a large scale.

But mRNA has potential beyond personalized medicine. From quick-turnaround applications like seasonal influenza vaccines to as-yet-untreated viruses such as Zika and previously “undruggable” diseases like enzyme deficiencies, its possibilities abound. In the long term, “most or all of the viral disease vaccines are up for grabs,” Porges says.

For mRNA vaccine makers, however, some properties may never be worth challenging. “Breaking in against, for example, Merck’s Gardasil or Glaxo’s Shingrix, that’s got to be more challenging, because the bar is already pretty high,” says Porges.

He expects mRNA vaccine developers to embark on preclinical research on those big-ticket properties, but the cost-benefit calculation for taking even a very effective vaccine into expensive and lengthy clinical trials will be different for conditions that already have effective vaccines. Gardasil has nearly 100% effectiveness in some cases, while Shingrix’s effectiveness is almost that high.

Any vaccine that confers more than 50% immunity is traditionally considered to be effective, but for existing markets with already highly effective options, the bar is much higher. mRNA experimentation is more likely to start with conditions without existing treatments and may never be conducted for some conditions for which highly effective vaccines already exist.

Wave of investment

At the beginning of 2020, mRNA vaccines had promise. But they had never been scaled before.

“Before COVID, there was no proof of concept,” says Adam Barker, a pharmaceutical analyst at Shore Capital.

“Most of the RNA vaccines were still in preclinical animal studies,” says Heaton. The few mRNA vaccines for infectious disease that had reached human trials, including for influenza and rabies, were in early stages. Cancer treatments and vaccines were also in trials.

And the technologies that made mRNA useful were just emerging. A reliable method for getting mRNA into cells—those tiny particles of fat, technically called lipid nanoparticles—had just been optimized by scientists in the late 2010s.

“I would estimate we were probably five to seven years away from having a licensed RNA vaccine in late 2019,” Heaton says.

The unprecedented collaborative environment and government investment prompted by the COVID-19 pandemic entirely changed that reality and provided both proof of concept for the vaccines, in the form of efficacy data and massive scale, in a matter of months.

“The fact that there was government support allowed manufacturers to scale up at risk, and to do that simultaneously while getting that first efficacy data,” Heaton says. That way, when Phase III studies were completed, and the drug was ready to be submitted for regulatory approval, companies were already stockpiling doses.

That kind of support allowed Moderna to rise from a small biotech to a prominent manufacturer who received the RNA portion of the DARPA contract that GE received for DNA. Elsewhere, says John Cooke, medical director of Houston Methodist’s RNA Therapeutics Program, academic interest and business investment in RNA research have spiked.

“There just seems to be a lot more momentum in the field,” he says. “It has attracted personnel and funding.”

Limitations

RNA vaccines and other therapies appear to have a bright future. But there are a number of limitations to their potential. “My biggest qualm right now is the temperature stability, the storage conditions, and the price,” says Heaton. “That said, these are problems that can be solved.”

Technology to keep the vaccines stable at higher temperatures can be developed. Vaccines can (and, many say, should) be subsidized.

Doing so could make a massive difference for global health and thus the global bottom line. Market-based strategies such as deeply subsidizing vaccine companies to produce vaccines for poorer countries have been proposed to quickly move on this issue, which will be an essential one, both financially and morally. “A key lesson of COVID-19 is that the great benefits the pharmaceutical sector has to offer must fully include the world’s poorest people,” two public health experts stated in a recent editorial proposing just this approach.

But even if technological change and advances in vaccine equity happen, Heaton also cautions that not all viruses will be as easy to target as COVID-19. The now-iconic spike protein represents a fairly simple mechanism for the SARS-CoV-2 virus to get into cells and begin replicating. Figuring out the correct parts of the virus to target and which specific viral RNA to use will be a much bigger challenge for many other viruses.

“It’s going to take innovation,” Heaton says.

Moderna was able to produce its first version of its vaccine just 42 days after the release of the SARS-CoV-2 genome’s sequence. That release, by a consortium of scientists headed by Yong-Zhen Zhang of the Shanghai Public Health Clinical Center & School of Public Health, was itself unusual evidence of collaboration between scientists.

Collaboration between academics, industry, and government has been the watchword of the last unprecedented year in vaccinology. Heaton says finding a way to continue that collaboration and build on it will be essential to maintaining the momentum of vaccinology’s golden age.

“A lesson isn’t learned until it’s actually applied,” she says, “until we decide what we are going to do differently.”

What’s next for mRNA vaccines? Since the COVID-19 pandemic is still very much ongoing, interrupting all facets of life, it’s hard to estimate the exact timeline. Barker anticipates that cancer treatments will be an early area of exploration, especially since there’s already so much data about mRNA and cancer. Personalized cancer vaccines were already in trial when the COVID-19 pandemic began, showing a high degree of effectiveness compared to other treatments.

But the widespread use of RNA vaccines for infectious diseases “ultimately depends on what the long-term data on the COVID vaccine is,” Barker cautions. Neither mRNA vaccine currently in use has received full FDA approval yet. Although we know they don’t hurt people and they do produce a high level of immunity, we don’t yet know how long-lasting that immunity is.

This uncertainty hasn’t stopped many drug companies from embarking on at least preclinical research, says Porges. When it comes to infectious diseases, he expects that seasonal influenza, cytomegalovirus, and tropical infectious diseases that don’t currently have a vaccine will be some of the first areas where we see results. But “it won’t be the case that every vaccine based on mRNA will have the same kind of strong response [as the COVID-19 vaccines],” cautions Barker.

Direct RNA treatments, which involve injecting unencapsulated RNA directly into the relevant organs, are already being trialed in humans, says Cooke. In 2019, Moderna’s treatment for heart regeneration in open-heart surgery patients passed through Phase I testing.

“With a 14-gauge needle and a strong arm, you can reach any area in the body,” Cooke says. Right now, lipid nanoparticles, if injected into your bloodstream, don’t do a great job of reaching any organs except the body’s filters, the liver and spleen, he says. That doesn’t matter for the COVID-19 vaccines, since they’re injected into the muscle of your arm and they start provoking immunity from there (that’s why some people get sore arms afterward). Targeted therapies need to be delivered directly. That could change: His team as well as others are working on new, more sophisticated formulations that would allow the drugs to be injected into the bloodstream and carried to the relevant part of the body—no 14-gauge needles involved.

When Katalin Karikó, the Hungarian-born scientist who risked her career to develop mRNA therapy, found out about the Pfizer vaccine’s efficacy, she was overjoyed. During the four decades of largely unacknowledged work, “I imagined all the diseases I could treat,” she told the Telegraph. Now and in the near future, Karikó, who now works for BioNTech, will watch an entire industry take her idea and run with it.