A modular three in one mucosal vaccine against three antigenic clusters of ACE2 using sarbecoviruses

Why this matters for everyday life

The COVID-19 pandemic showed how quickly a new coronavirus can spread worldwide and upend daily life. Scientists also know that many related viruses are still circulating in bats and other animals, any of which could spark the next outbreak. This study describes a needle-free nose spray vaccine designed to protect against a broad group of these coronavirus cousins at once, aiming to make future pandemics less likely and less severe.

A hidden family of threat viruses

SARS-CoV-2, the virus that causes COVID-19, belongs to a larger family called sarbecoviruses. Many members of this family, especially those that can use the human ACE2 protein to enter our cells, are found in bats and other animals. Existing immunity from infection or current vaccines often does a poor job neutralizing these distant relatives, leaving a gap in our defenses. The authors first mapped how the key surface segments of these viruses—regions that latch onto ACE2—differ from one another. They found that ACE2-using sarbecoviruses fell into three major clusters, each representing a distinct "flavor" of the receptor-binding region.

Building a three-in-one nose spray

Instead of trying to invent a single universal vaccine for every coronavirus, the team pursued a modular approach. They chose one representative virus from each of the three clusters: the Omicron BA.1 variant of SARS-CoV-2 and two SARS-like bat viruses called WIV1 and RsSHC014. They then stitched the three corresponding binding regions into a single protein scaffold, creating a combined immunogen they call 3Rs-NC. Computer modeling and antibody tests showed that each of the three segments kept its original three-dimensional shape, an important sign that the immune system would recognize them as if they were part of real viruses.

Strong protection in the nose, lungs, and blood

The researchers tested their new construct in mice, comparing it with mixtures of the same three components given separately and with an earlier triple design focused only on SARS-CoV-2 variants. When delivered with a standard aluminum adjuvant into muscle, the three-in-one protein triggered higher and broader neutralizing antibodies against all three test viruses than either comparison. The most striking effects appeared when 3Rs-NC was dripped into the nose together with KFD, a flagellin-derived substance that safely boosts immune responses on mucosal surfaces. This intranasal pairing produced coordinated immunity in blood and at mucosal sites: high levels of protective antibodies in serum, as well as antibody responses in saliva, the nose, and the female reproductive tract.

Lasting defense and differences between sexes

To see whether these responses translated into real-world protection, the team challenged specially engineered mice that express human ACE2 with live viruses. Mice that received the nose spray vaccine showed sharply reduced virus levels in both lungs and nasal tissues after exposure to Omicron BA.1 or WIV1, while muscle-injected animals mainly gained protection in the lungs. In a separate experiment with a lethal dose of RsSHC014, vaccination by either route greatly improved survival compared with unvaccinated controls, with especially strong protection in female mice. Remarkably, antibody levels in nose-sprayed animals stayed high for at least a year, and these animals remained protected against Omicron infection in both upper and lower airways long after the last dose.

What this means going forward

For non-specialists, the key message is that the researchers have created a single, needle-free nasal vaccine that protects laboratory animals against three different clusters of high-risk SARS-like coronaviruses at once, and does so for a very long time. Rather than offering a one-shot cure-all, their work supports building a shelf of modular vaccines, each tuned to a subset of related viruses. In the face of a new coronavirus threat, public health officials could quickly select the most appropriate candidate from this package and deploy it as a protective nasal spray, potentially buying crucial time and limiting the impact of future outbreaks.

Citation: Liu, L., Lin, H., Li, M. et al. A modular three in one mucosal vaccine against three antigenic clusters of ACE2 using sarbecoviruses. npj Vaccines 11, 76 (2026). https://doi.org/10.1038/s41541-026-01403-1

Keywords: mucosal vaccine, sarbecovirus, intranasal immunization, broadly neutralizing antibodies, ACE2-using coronaviruses