Scientists envision a shot that could protect against many coronaviruses in one fell swoop.

The Covid-19 vaccines available today are amazing feats of science. Researchers achieved in less than a year what can sometimes take decades: They targeted a new virus with multiple highly effective vaccines that have reached billions of people. They deployed new approaches like using messenger RNA and adenovirus vectors at large scales for the first time, making some of the biggest leaps in vaccine technology in hundreds of years.

But the limitations of these vaccines are becoming apparent, which is why some scientists are calling for an even bigger leap forward in vaccine technology. They envision a universal coronavirus vaccine that could counter every known variant of the virus that causes Covid-19, and even variants that haven’t emerged yet. It’s possible such a vaccine could protect against the whole family of coronaviruses, bolstering long-term immunity and slashing the risks of similar pandemics in the future.

This work is urgent because scientists are finding that protection from Covid-19 vaccines fades over time. And the virus itself is changing, mutating in ways that make it harder for the immune system to counter. The omicron variant has already caused breakthrough infections in large numbers of vaccinated people, and it’s a matter of time before the virus mutates again.

“We must now prioritize development of broadly protective vaccines like the universal influenza vaccines we have been working toward in recent years,” wrote National Institutes of Health researchers David Morens, Jeffery Taubenberger, and Anthony Fauci in the New England Journal of Medicine last month.

This crucial work is a long shot. It hinges on breakthroughs in technology and our current understanding of the immune system, because there’s a lot researchers still don’t know about how our cells defend us from infection. And the universal vaccine approaches that scientists are experimenting with — from universities and even the US Army — have never been used on large scales before.

Even the faint hope of preventing another global cataclysm — and contributing to the end of the one we’re living through now — deserves money and scientific attention, researchers told Vox. It could take years of sustained effort, but some researchers are confident that universal vaccines will emerge.

How do you make a universal coronavirus vaccine?

Before Covid-19 came along, vaccines followed a standard formula. They introduced the immune system to viral threats by injecting weakened or dead viruses, or virus fragments, into the body.

The Covid-19 pandemic was the dawn of a new era of vaccines. Adenovirus vector vaccines (like the one from Johnson and Johnson) and mRNA vaccines (like the ones from Moderna and Pfizer/BioNTech) deliver genetic instructions to human cells, so they can produce a fragment of SARS-CoV-2, the coronavirus that causes Covid-19. The immune system uses these components for target practice. If the real pathogen arrives, the immune system has an action plan.

The challenge, even with these new vaccine platforms, is that the target practice is very specific, and it doesn’t always translate from one variant to another. If a virus mutates, vaccines can become less effective at stopping disease. Hence the need for a vaccine that can cover a spectrum of threats.

The first task in developing a universal vaccine is deciding how universal to make it. Will it be a vaccine aimed at all the variants of SARS-CoV-2? A vaccine for the broader category of sarbecoviruses that include the pathogens that cause SARS and MERS? Or a vaccine for the entire betacoronavirus genus?

“When we say universal vaccines, the word ‘universal,’ we have to put it in air quotes,” said Morens, who is a senior adviser to Fauci and a professor at Johns Hopkins Bloomberg School of Public Health. “If we were to make a universal vaccine now, the first thing we’d want to do is have it be universal enough to cover all the strains that are circulating in people.”

But the wider the scope of the vaccine, the bigger the challenge.

Most Covid-19 vaccines train the immune system to identify the spike protein of the virus. This is the part of the virus that physically sticks out and starts the infection process by docking with a receptor on human cells. In a vaccine, the spike serves as an antigen — a component that activates the immune system.

Once the virus is identified, the immune system starts making proteins called antibodies. They bind to particular parts of the virus known as epitopes. If the antibodies interfere with the virus enough that they prevent it from causing an infection, they’re called neutralizing antibodies.

The spike protein is easily recognizable for the immune system, so vaccines that target it can generate robust protection. But vaccines also spur the virus to evolve, yielding an advantage to mutated spike proteins that are harder for the immune system to recognize. As a result, the spike protein of SARS-CoV-2 has been one of the fastest-mutating parts of the virus, making it a moving target for the immune system.

Scientists are trying two main approaches to get around this problem, according to Deborah Fuller, a professor of microbiology at the University of Washington School of Medicine.

Strategy 1: Train the body to recognize a mosaic of spike proteins from many variants

One approach is to combine multiple antigens in a single shot. “You simply take as many spike proteins from as many different coronaviruses that are out there, and you decorate a virus-like nanoparticle protein with all of them,” Fuller said. The idea is that if the immune system tastes a sampler platter of enough distinct spike proteins, it will learn to fill in the blanks and cover most, if not all, potential mutations in SARS-CoV-2.

“There is a limit to the number of mutations it can eventually develop to fully evade the immune system, without compromising its own ability to attach to and infect cells,” Fuller said. “Once you get to a certain number of spike proteins, you get all the possible mutations represented within those.”

Using computational biology, scientists can simulate the spectrum of mutations and select the structures that have the greatest chances of providing broad-based immunity.

This is the approach that the US Army is currently investigating by attaching different SARS-CoV-2 spikes to a protein called ferritin. Its vaccine is currently in early clinical trials. (US Army researchers declined to comment until they finished analyzing their early results.)

Strategy 2: Vaccinate against parts of the coronavirus that don’t mutate

The other strategy is to target parts of the virus that stay the same even when the virus evolves, or the parts in common with its relatives (scientists describe these parts as “conserved”). This is the approach Fuller is studying in her laboratory.

Conserved regions are often parts of the virus that are critical to its function; the virus ceases functioning if they mutate. “If you target the parts that are conserved, then that would have, theoretically, protective efficacy against any of the coronaviruses that are out there,” Fuller said. That could extend to every past and future variant of SARS-CoV-2 and the broader group or family of coronaviruses it belongs to.

These conserved regions might be buried on parts of the virus that are less visible to the immune system, or physically difficult for antibodies to access when the virus is whole. But when a virus invades a cell and begins the infection process, fragments of the pathogen can show up on the outside of the host cell, including parts that were previously obscured. Antibodies can then attach to those fragments and get to work.

Such antibodies are described as non-neutralizing because they don’t prevent infection in the first place. But they recruit other players in the immune system, including B cells that manufacture antibodies and T cells that eliminate infected cells.

A universal vaccine that targets conserved regions might not prevent infection, according to Fuller, but it could turn dangerous coronaviruses into bugs that mostly cause minor illnesses. “It builds a level of immunity in the population such that anytime a coronavirus outbreak should occur, it really doesn’t have the fangs anymore to cause a pandemic,” she said.

Sounds straightforward enough, but there are many complications. First, not every conserved region makes a good antigen. Some will be completely ignored by the immune system and fail to generate a response. Second, scientists have to study the whole spectrum of coronaviruses to find out exactly which portions of the virus stay the same. Third, the immune system’s response to a conserved region might not be effective against an infection.

“If we can figure all that out — I’m confident we can — then we can design a universal coronavirus vaccine” that targets conserved regions, Fuller said.

It’s remarkably difficult to vaccinate against respiratory infections

There’s a big difference between drugs that treat illnesses and vaccines that try to prevent them. A doctor would only prescribe a treatment like chemotherapy, for example, after a patient has been diagnosed with advanced cancer; there are just too many risks and side effects for someone in an earlier stage of the disease to take such harsh medicines.

Vaccines, by contrast, are meant to prevent disease in billions of people. Regulators will only approve them if the risks are extremely low and side effects are extremely rare.

As a result, vaccine research is historically slow and expensive. The development costs are high, the timelines span decades, and the payoff is never guaranteed. That is, until Covid-19 came along and triggered a radical shift in this paradigm.

The urgency of the pandemic condensed the vaccine development timeline by injecting cash, inspiring many teams to join the effort, and by lowering administrative hurdles. The research supported by programs like Operation Warp Speed yielded a new generation of vaccines in record time. Beyond funding research on vaccine candidates, the US government promised to purchase millions of doses of their vaccines, even if some of those shots didn’t work out.

But the big limitation of current Covid-19 vaccines is that they were originally designed for the early versions of SARS-CoV-2. These vaccines may not be enough to contain a virus that’s constantly changing, especially since a large segment of the global population remains unvaccinated.

Respiratory viruses are also unusually challenging beasts. They tend to infect the outer cells of airways, known as the epithelium, rather than penetrating deeper into the body. Scientists theorize that the immune system has a harder time getting a lock on these pathogens and maintaining long-term protection after they pass.

“They’ve got a great trick,” Morens said. “They can infect us and cause disease, and make us cough and sneeze and force us to spread them around to others, and they don’t have to fight the big fight with our immune system.”

Then there’s the problem of vaccine testing. In the US, between the 249 million people who have received a Covid-19 vaccine and 67 million Covid-19 cases, the vast majority of the population has been exposed to some part of the virus. That means it’s going to be much harder to find people with zero immunity to the SARS-CoV-2 virus who can participate in a control group in a clinical trial. (There are workarounds — scientists manage to study cold pathogens and flu viruses even though countless people have antibodies to them — but they require different experimental protocols.)

All of this makes for a huge scientific challenge. Scientists have already been trying for years without success to develop a universal influenza vaccine. And there are many fundamental mysteries still lurking in this area of immunology.

Even a universal vaccine isn’t a silver bullet

Devoting more resources to universal vaccine research is critical, but such vaccines depend on breakthroughs and discoveries, too, so there’s no guarantee that they will come to fruition. “To make a universal vaccine is an order of magnitude more complicated,” Morens said. “Science has never been able to make a universal vaccine to anything, ever.”

And while vaccines are a critical way to keep an infectious disease in check, even a successful universal shot might not be enough to extinguish a pandemic and prevent the next one. For one thing, it’s not clear how long protection from such a shot would last.

“You could have a universal vaccine that covers every single coronavirus, but if the immunity it elicits wanes, it’s not that good,” Morens said. “I would define a universal vaccine not only to cover all the viruses, [but also] to induce durable immunity.”

Then there’s the question of how to deploy a universal vaccine. Would we need another vaccination campaign to get this shot into everyone’s arms, or would it be limited to people in high-risk groups? That might depend on the performance of the vaccine, as well as the state of the health care system and the level of coronavirus transmission. “Public health policies [would] have to be developed to decide who should be vaccinated,” Morens said.

And as we’ve learned from existing Covid-19 vaccines, it’s still important to limit transmission with social distancing and wearing face masks. Testing and sequencing remain critical for understanding the spread and evolution of the virus.

A universal coronavirus vaccine could eventually become one of public health’s most powerful tools. But it will need to work in tandem with all of the other strategies that have proven useful in the past two years.