Every time a new variant comes along, COVID-19 vaccine and drug makers reassess their “recipes” to see if they work against an evolving virus—like Omicron, which has spread quickly around the globe in little more than a month.
Since the start of the pandemic in December 2019, the SARS-CoV-2 coronavirus that causes COVID-19 has mutated multiple times, giving rise to different variants. Because most vaccines were designed to recognize the original SARS-CoV-2 spike protein, or at least parts of it, more mutated variants like Omicron are better at escaping protection offered by the vaccines, although they still prevent severe disease.
Last month, vaccine makers talked about tweaking the formula to have an Omicron-specific vaccine handy, if needed. “But Omicron won’t be the last variant,” says Stephen Zeichner, an infectious disease specialist at the University of Virginia Medical Center. “It’s pretty clear that the virus continues to evolve and going forward there is a need for a universal COVID-19 vaccine or even a universal coronavirus vaccine.”
Since 2020, in preparation for the next deadly coronavirus outbreak, which experts think is only a matter of time, some scientists started developing vaccines that protect against multiple coronaviruses. Many efforts currently focus on known sarbecoviruses, which include SARS-CoV-1 and SARS-CoV-2, and some SARS-like bat viruses that have the potential to jump from animals to humans.
Early tests in animal models are showing promising results. “The great thing about having such vaccines is that they could handle potentially new [SARS-CoV-2] variants as well as the next horrible spillover viruses that’ll come down the road,” says structural biologist Pamela Björkman at the California Institute of Technology, who is developing a universal vaccine for some SARS-like viruses.
Blocking new variants and future coronaviruses with spillover potential
Omicron, the latest version of the virus classified as a variant of concern by the World Health Organization on Nov. 26, 2021, has nearly 50 genetic mutations compared to the original SARS-CoV-2 strain. More than 30 of these are on the club-shaped spikes protruding from the virus’ surface that facilitate its entry into host cells. The spike is also the region of the virus that COVID-19 vaccines target to prevent serious disease.
Human coronaviruses were first identified in the mid-1960s and rarely caused severe disease. But that changed in 2002, when a fatal respiratory illness caused by a new coronavirus SARS-CoV linked to cave-dwelling bats emerged in China and spread to 29 countries, infecting nearly 8,000 people, and leaving more than 700 dead. A decade later, another new coronavirus, MERS-CoV—that emerged in Saudi Arabia and presumably originated in bats—has infected more than 2,000 people in 37 countries and killed nearly 900 to date. The danger posed by coronaviruses originating in animals became even more apparent with SARS-CoV-2, which has resulted in nearly 332 million confirmed worldwide cases and more than five million deaths since its emergence in late 2019.
While short-sightedness and limited funding have hindered the development and testing of these vaccines, recent investments like the non-profit Coalition for Epidemic Preparedness Innovation’s $200 million program and the National Institutes of Health’s $36.3 million research fund means that pan-coronavirus virus vaccines—at least for SARS-like viruses—may be a reality sooner than many imagined.
One vaccine, multiple coronaviruses
The goal of such vaccines is to generate a broad immune response against multiple coronaviruses and its variants.
The effort that is farthest along is a vaccine developed by researchers at the Walter Reed Army Institute of Research, which has been tested in humans as part of a Phase I trial. The vaccine, which borrows technology developed for making universal flu vaccines, entails a soccer ball-shaped nanoparticle with 24 faces decorated with multiple copies of the original SARS-CoV-2 spike protein. Peer reviewed research conducted in monkeys showed the vaccine’s ability to generate antibodies that neutralize and block the entry of SARS-CoV and SARS-CoV-2 and its major variants (excluding Omicron, which was not tested) into animal cells. “The repetitive and ordered display of the coronavirus spike protein on a multi-faceted nanoparticle may stimulate immunity in such a way as to translate into significantly broader protection,” Kayvon Modjarrad, co-inventor of the vaccine, stated in a press release. His team is currently analyzing the Phase I data. National Geographic reached out to Walter Reed multiple times for more details, but they declined to comment until the results of the Phase I trials are published.
Other universal coronavirus vaccine efforts involve targeting a slow evolving, genetic and structurally similar region on the viruses—where antibodies bind as part of a body’s immune response to a foreign invader—or additionally engaging the body’s immune cells called T cells.
Zeichner, for instance, is focusing on the fusion peptide region, which is part of the coronavirus spike protein that aids the entry of the virus into host cells, to develop a pan-coronavirus vaccine. “It is extremely conserved among all coronaviruses,” he says. “It doesn’t mutate very much.” Along with colleagues, he tested a proof-of-concept vaccine using a SARS-CoV-2 fusion peptide and early results indicated that in pigs the vaccine provided some protection against a different coronavirus, called porcine epidemic diarrhea virus, that doesn’t infect humans. His team is now collaborating with researchers at Virginia Tech and the International Vaccine Institute in Seoul to further develop and continue testing the vaccine against different SARS-CoV-2 variants and other coronaviruses.
Björkman and her colleagues, on the other hand, are focusing on a more specific target: the spike protein’s receptor-binding domain (RBD). It’s the region of the spike to which most antibodies bind to prevent SARS-CoV-2 from entering the host cell; it is also the region within which mutations occur, giving rise to variants. For the vaccine, they used RBD proteins from up to eight viruses—including the original SARS-CoV-2 and other SARS-like coronaviruses isolated from bats—that were fused onto a nanoparticle with 60 faces. By injecting this vaccine into mice, Björkman and her colleagues found the animals produced diverse antibodies, which in follow-up experiments blocked infections caused by several SARS-like viruses, including coronavirus strains not used to create the vaccines.
To Björkman, this suggests that the animal’s immune system might be learning to recognize common features between the coronaviruses and that her mosaic vaccine, with pieces selected from multiple viruses, might be useful when new SARS-like viruses or new SARS-CoV-2 variants emerge. Her team is currently gearing up to test the vaccine in humans.
Vaccine researcher Kevin Saunders at the Duke Human Vaccine Institute is also focusing on the RBD, but a very specific part of it, to make a pan-SARS-like virus vaccine. When the pandemic began in early 2020, Saunders and his colleagues began hunting for antibodies that would inactivate SARS-like viruses. They examined antibodies present in frozen stored cells of an individual who recovered from SARS-CoV infection and another individual previously infected with COVID-19.
They identified a potent antibody dubbed DH1047 occurring in cells from both patients that could block infections in which mice that had been injected with several bat and human coronaviruses, including SARS-CoV-2 variants. A closer look revealed the antibody bound to the same small section of the spike protein’s RBD in different coronaviruses, which became the vaccine target.
By injecting monkeys with multiple copies of this SARS-CoV-2 RBD piece fused to a nanoparticle, Saunders and his colleagues demonstrated the vaccine’s ability to protect against not just SARS-CoV-2 but several other coronavirus infections. The team is now testing different iterations of this nanoparticle vaccine by introducing RDB sections from other coronaviruses to broaden the host’s immune response.
“Sometimes you make hundreds of versions of these [vaccines] and test them in animals before deciding on a version to study in humans,” says Julie Ledgerwood, deputy director and chief medical officer at the National Institutes of Health’s Vaccine Research Center. It’s not simple, she says.
Meanwhile, scientists are also trying to figure out how these vaccines could cover not just SARS-like viruses but MERS and other more distantly-related coronaviruses too. “The sequence diversity and structural differences between coronaviruses that fall into different groups is going to be a challenge,” Saunders says. Some scientists propose a different vaccine for different coronavirus families.
For now, though, the need for at least a pan-SARS-like coronavirus vaccine cannot be ignored. “We’re no longer thinking of this as ‘it’ll be great to have this for the next pandemic,’” Saunders says. “We’re thinking of this as a great tool to stop this pandemic.”