In early 2003, a deadly respiratory illness began spreading in China, raising alarm bells among health authorities around the world. After cropping up in 29 countries, the coronavirus that caused the illness, now known as SARS-CoV-1, infected more than 8,000 people and killed more than 700. Less than 10 years later, in 2012, another deadly coronavirus, MERS-CoV, emerged—killing hundreds more.
Then, in 2019, came SARS-CoV-2, a related virus whose devastation has vastly outstripped that of its predecessors. Based on the latest tallies, the virus has infected more 100 million people and caused more than 3.8 million deaths. “In less than 20 years, we have seen three major outbreaks from three different coronaviruses,” says Pablo Penaloza-MacMaster, a viral immunologist at Northwestern University. “The question is not whether there will be a next coronavirus pandemic. The question is when.”
To better prepare for the next deadly outbreak, some scientists are working on developing a universal coronavirus vaccine: a shot that will protect us not only from SARS-CoV-2, but also from any potentially dangerous relatives that may emerge in the future. These efforts are mostly in their early stages as researchers tinker with their designs and test their formulations in animals—although at least one vaccine that generated immune responses against SARS-CoV-2 variants and SARS-CoV-1 in animal studies recently entered a Phase 1 clinical trial.
“Just having those ready for when the next one comes will be critical to prevent this from happening again,” says Penaloza-MacMaster.
A deadly family
There are four families, or genera, of coronaviruses: alpha, beta, gamma, and delta. All seven coronaviruses known to infect humans belong to either the alpha or beta families. The two in the alpha family, 229E and NL63, both cause common colds. The beta family is more problematic for humans: It includes two common cold viruses, OC43 and HKU1, as well as all three viruses with higher fatality rates that have caused deadly outbreaks in humans: SARS-CoV-1, SARS-CoV-2 and MERS-CoV.
The ultimate universal vaccine would protect against all coronaviruses, but the genetic diversity that exists among the four groups makes such a goal very difficult to achieve. Instead, most research groups have zoomed in on the beta coronaviruses—and, more specifically, a subgroup known as sarbecoviruses that includes SARS-CoV-1 and SARS-CoV-2, which are more genetically similar to one another than to MERS-CoV, OC43, or HKU1. Kevin Saunders, a vaccine researcher at the Duke Human Vaccine Institute in North Carolina, says that he sees the universal coronavirus vaccine efforts as going forward in two phases: first focusing on finding a vaccine for sarbecoviruses, then broadening to MERS-like beta coronaviruses.
It may be possible to one day generate a truly universal coronavirus vaccine. But before that happens, “a lot of research has to be done to figure out how far you can push this kind of cross-reactive immune recognition,” says Pamela Björkman, a structural biologist at Caltech.
A recent study by Penaloza-MacMaster and his colleagues, posted as a preprint on bioRxiv, provided evidence that a vaccine against sarbecoviruses—and even for betacoronaviruses more generally—may be achievable. In mice, they demonstrated that various SARS-CoV-2 vaccines, including mRNA vaccines such as the shot from Pfizer/BioNTech and viral-vector vaccines such as Johnson & Johnson’s version, generated immune responses against SARS-CoV-1 and OC43.
The team also showed that a viral-vector vaccine against SARS-CoV-1 protected mice from SARS-CoV-2 infections, as measured by levels of virus detectable in the lungs—and that viral vector–based SARS-CoV-2 vaccines reduced viral load in animals after OC43 infections. The protection immunization provided wasn’t equal; the more similar the viruses were genetically, the higher the level of cross-protection provided by a vaccine: The protection the SARS-CoV-1 shot gave against SARS-CoV-2 was much stronger than what the SARS-CoV-2 shot provided against OC43. “These data suggest that it is reasonable to think that universal coronavirus vaccines are possible, [and that] the maximum degree of protection will be proportional to the genetic distance between the different coronaviruses,” Penaloza-MacMaster says.
Another study, which Saunders and his colleagues recently published in Nature, also provides an important proof-of-concept demonstration that a pan-coronavirus vaccine is feasible. The researchers developed a candidate vaccine, which included a nanoparticle with its surface covered in copies of a site on the receptor-binding domain of the spike protein—the part of the virus that recognizes and binds to receptors on our cells—that is highly conserved across sarbecoviruses, as well as an immune response–boosting adjuvant. In monkeys, that vaccine generated an immune response against multiple coronaviruses—SARS-CoV-1, SARS-CoV-2, and sarbecoviruses found in bats. Saunders says his group is currently in talks with both private companies and the US National Institutes of Health about moving the vaccine candidate forward into a clinical trial.
Rallying the body’s defenses
There are various efforts for a universal coronavirus vaccine ongoing, but the general goal is the same: to induce the broadest immune response against a wide array of viruses. There are two ways that vaccines can make this happen: either stimulating the production of antibodies, proteins that recognize foreign invaders and attack them before they infect a cell, or recruiting T cells, a type of immune cell that shows up later to destroy cells after they’ve become infected.
T cells will not prevent an infection, but they tend to be better at identifying conserved regions of viruses that may slide past antibodies, according to Deborah Fuller, a vaccine researcher at the University of Washington. “T cell responses are great, because unlike antibodies, which have to some extent a more limited repertoire, T cells will actually recognize parts of the virus that get broken down inside the cell,” Fuller explains. Antibodies are “very specific to one type of variant—sometimes they can be cross-reactive to multiple variants—but [for a pan-coronavirus vaccine] what you really want to do is engage that T cell response.”
Fuller and her colleagues are combining two approaches. One uses the nucleic acid technology seen in currently available mRNA-based COVID vaccines, which present key regions in the spike protein for the cell for manufacture. According to Fuller, there’s evidence suggesting that one reason mRNA vaccines protect against SARS-CoV-2 variants is that they induce a T cell response. The other, the focus of a collaboration between Fuller and Neil King at the Institute of Protein Design, involves studding a nanoparticle with spike proteins from different sarbecoviruses to induce a wide range of specific antibody responses.
Björkman’s team is testing an approach in which receptor-binding domains from eight different sarbecoviruses are attached to a nanoparticle. The receptor binding domain is not as big as the spike, so according to Björkman, it won’t have as many regions that are recognized by T cells, which are known as T cell epitopes. “That being said, if you have eight different receptor binding domains, you are going to have more potential T cell epitopes.” Whether that mosaic vaccine will generate a stronger T cell response than a single-virus vaccine is one of the questions that Björkman’s team is hoping to address in rodents and later monkeys.
That there are parallel efforts to develop a universal coronavirus vaccine is a positive thing, says Penaloza-MacMaster, whose group is working on a vaccine that expresses both the spike protein and other segments of SARS-CoV-2—such as the nucleocapsid, an internal protein that is more conserved among viruses than the spike protein is. “One lesson that we have learned from this pandemic is that it’s good to have your eggs in different baskets,” he tells The Scientist. “We see the success of multiple vaccine platforms and high efficacy against SARS-CoV-2—part of that is because our field tried several different approaches.”
The road ahead
Creating universal vaccines is a difficult task. Influenza researchers, for example, have spent decades attempting to develop a shot that would provide protection across multiple flu seasons. The first Phase 3 trial of a pan-influenza vaccine began just a few years ago, in 2018. Although that vaccine ultimately failed to show efficacy, several other universal flu shots are now in late-stage clinical trials.
One of the biggest challenges with flu has been the genetic diversity of influenza viruses that has arisen due to their ability to rapidly mutate and evade the body’s defenses. The good news is that although coronaviruses also mutate—as is clear from the continuous threat from new variants of SARS-CoV-2—they do so at a much slower rate than influenza viruses do. One of the reasons for this is that coronaviruses contain a proofreading enzyme that corrects for errors that occur when it replicates.
“SARS-CoV-2 seems a little bit like lower-hanging fruit because influenza undergoes considerably more diversification,” says Fuller, whose work includes developing a universal influenza vaccine. “A universal vaccine [for influenza] is to some extent trickier, because you have to take into account a lot more lineages and variants that are already circulating or could emerge in the future as a pandemic.”
Another key issue to consider is a phenomenon known as antibody-dependent enhancement (ADE), in which existing antibodies can make future infections more severe. Concerns about possible ADE was one of the factors that stymied efforts to develop vaccines for SARS-CoV-1 and MERS, according to Saunders. The worry was that “if you vaccinate and the immune response isn’t really, really potent, it may not be a helpful response and may actually make infection worse.”
However, although there is some evidence that ADE occurs with MERS, “for SARS-CoV and SARS-CoV-2, that doesn’t seem to be the case,” Saunders says. Nonetheless, he adds, researchers are closely monitoring for ADE in their vaccine development efforts.
There are also some practical challenges—trying to create a vaccine for a yet-unknown virus means that it is impossible to test the efficacy of these immunizations in the way that existing COVID-19 vaccines have been tested: through clinical trials that determine how many people become ill or infected with the target viruses after receiving a vaccine.
“The best we can do is survey the viruses that we know about and try to make an educated guess [about] a future virus,” Saunders says. One of the ways to test the efficacy of a vaccine against a yet unknown pathogen will be to vaccinate people, then collect serum samples from them—fluid from the lungs and other parts of the mucosal surface—and see what types of antibodies are there, according to Saunders. “Then you can actually characterize what those antibodies can do.” This means taking those antibodies and testing whether they protect lab animals, such as mice or monkeys, from as many different coronaviruses as possible.
Some researchers, including Andrew Ward, a structural biologist at Scripps Research, are focusing their efforts more on understanding how humans respond to existing viruses, looking at past infections to better predict how people will respond to new virus in the future. Although people generate immunity and antibodies to seasonal infections, “that’s not very durable—it lasts about a year then wanes,” Ward says. “We’re really interested in which are the elements, the types of antibodies, the targets on the spike—that are more durable and more likely to give you pan-coronavirus immunity.”
The goal of this work, according to Ward, is not necessarily to develop a pan-coronavirus vaccine, but to better understand our immune responses to coronaviruses in order to be prepared to rapidly generate new vaccines as soon as new viral threat emerges. “We don’t really know where the next pandemic is coming from, just like we didn’t expect this one, to the extent that it happened,” Ward says “Being more prepared through surveillance, and then being able to translate quickly [to make a vaccine], I think is the smart thing to do.”
Much more research remains to be done before the world is prepared for the next deadly outbreak. “What I’m most hopeful about is that we now have the infrastructure and resources in place and we know what types of things we would need in order to fight against a pandemic or an outbreak,” Saunders says. “Hopefully we’ll keep those resources at hand so that, seven to ten years from now, if another outbreak occurs, we’re ready.”
Clarification (June 30): This story was updated to note that Fuller’s work on nanoparticles is in collaboration with Neil King.