A pan-coronavirus vaccine—one that provides protection against a number of different coronaviruses—is public health’s holy grail. To be effective, the vaccine would need to trigger antibodies that recognize and neutralize a range of coronaviruses, stopping the virus from entering hosts cells and replicating. This type of vaccine is a challenge to develop for coronaviruses, in part, because they frequently mutate and generally induce incomplete protection against reinfection.

Although antibody cross-reactivity with the Spike proteins of different coronaviruses, including the common cold coronaviruses (HCoVs), has been shown, the authors of a new paper noted that it is unclear “whether such antibody responses, typically targeting the conserved S2 subunit, contribute to protection when induced by infection or through vaccination.”

Now, researchers have investigated whether antibodies that target the S2 subunit of SARS-CoV-2’s spike protein also neutralize other coronaviruses. This specific area of the spike protein tethers it to the virus membrane and allows the virus to fuse with the membrane of a host cell.

The researchers said their findings “establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern, as well as to future coronavirus zoonoses.”

The study titled, “SARS-CoV-2 S2-targeted vaccination elicits broadly neutralizing antibodies,” is published in Science Translational Medicine. 

“The expectation for a vaccine that targets the S2 area is that it could offer some protection against all current, as well as future, coronaviruses,” noted George Kassiotis, PhD, principal group leader at the Francis Crick Institute. “This differs from vaccines that target the more variable S1 area which, while effective against the matching variant they are designed against, are less able to target other variants or a broad range of coronaviruses.”

The S2 area of the spike protein has, until recently, been overlooked as providing a basis for vaccination. This is because certain critical targets in the S2 area are only revealed after the virus has bound to a cell, a process mediated by the S1 area. As a result, there may be a narrower window of opportunity for S2 antibodies to neutralize the virus than for antibodies that target the S1 area.

Using a mouse model, the team found that prior HCoV-OC43 S–targeted immunity “primes neutralizing antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses.”

After vaccinating mice with SARS-CoV-2 S2, the mice created antibodies that were able to neutralize a number of other animal and human coronaviruses, including: the seasonal “common cold” coronavirus HCoV-OC43, the original strain of SARS-CoV-2, the D614G mutant that dominated in the first wave, Alpha, Beta, Delta, the original Omicron, and two bat coronaviruses.

“The S2 area of the spike protein is a promising target for a potential pan-coronavirus vaccine because this area is much more similar across different coronaviruses than the S1 area,” noted Kevin Ng, a PhD student in the retrovirus laboratory at the Francis Crick Institute. “It is less subject to mutations, and so a vaccine targeted at this area should be more robust.”

Lastly, in mice with a history of SARS-CoV-2 Wuhan–based S vaccination, further S2 vaccination induced broader neutralizing antibody response than booster Wuhan S vaccination, suggesting that “it may prevent repertoire focusing caused by repeated homologous vaccination.”

“While a potential S2 vaccine would not stop people being infected, the idea is it would prime their immune system to respond to a future coronavirus infection,” added Nikhil Faulkner, a PhD student in the retroviral immunology laboratory at the Crick. “This would hopefully provide enough protection to survive an initial infection during which they could develop further immunity specific to that particular virus.”

The researchers will continue this work studying the potential of a pan-coronavirus that targets the S2 area of the spike protein and how it could be integrated with currently licensed vaccines.