A single intranasal dose of a live-attenuated broad-spectrum coronavirus vaccine developed at the University of Hong Kong (HKU) elicits broad, potent and long-lasting immunity against diverse SARS-CoV-2 variants of concern (VoCs) and more divergent SARS-CoV-1 and hCoV-OC43 that translates into complete protection in animal models, including prevention of viral transmission to unvaccinated contacts.
“Current COVID-19 vaccines have saved countless lives but primarily aim to induce immunity to the virus’s spike protein or its receptor-binding domain [RBD], and often fail to confer broad or durable protection against rapidly evolving variants and prevent transmission,” wrote the researchers. [Lancet Infect Dis 2022:22;1293-1302; N Engl J Med 2022;387:21-34] “To address these concerns, we rationally designed a live-attenuated pan–beta-CoV mucosal vaccine candidate by changing the codon usage bias of SARS-CoV-2 viral genome.” [Proc Natl Acad Sci U S A 2026;27;123:e2518645123]
The research team successfully generated five mutant viruses that exhibited varying degrees of attenuation in vitro, ranging from moderate to high levels. One highly attenuated candidate, cb1, was not associated with weight loss or other clinical signs in infected K18-hACE2 mice regardless of the infection doses, and was only recoverable in trace amounts from the mice’s nasal turbinates and lungs, with no evidence of histopathology during acute phase. As a result, cb1 was selected as the vaccine candidate for all subsequent studies.
cb1 immunization led to high neutralization (40–90 percent) of early VoCs, including wild-type, Alpha, Beta, Delta, Delta+, and Lambda, and good neutralizing activity against the RBD of sarbe-CoVs, Pangolin CoV, but this activity gradually decreased against progressive Omicron VoCs. However, the robust, cross-reactive T-cell immunity, which was observed in response to cb1 immunization in a separate set of experiments, likely compensates for the limited neutralizing antibodies against divergent Omicron variants and SARS-CoV-1, thereby conferring complete heterologous protection. Furthermore, the increase in IL-4–secreting CD4+ T-cells in the spleen in response to mouse-adapted hCoV-OC43 demonstrated that vaccine successfully mounted a Th2 cross-reactive response to other beta-CoVs.
“Our codon-deoptimization strategy allowed us to substantially weaken the virus without changing a single amino acid. The vaccine replicated only to the extent needed to comprehensively train the immune system, while remaining too weak to cause disease. The observed breadth of protection spanning multiple species of beta-coronaviruses is exceptionally promising for the development of a universal coronavirus vaccine,” stated Professor Leo Poon of the School of Public Health at HKU.
The researchers also explored whether mucosal vaccination with cb1 blocks onward spread during continuous, prolonged direct contact by placing infected donor Syrian hamsters 24 hours post-immunization in a clean cage with naïve animals for 14 consecutive days. Naïve recipients paired with cb1-vaccinated donors showed no weight loss and no detectable virus in oral swabs, whereas those housed with mock-vaccinated donors lost weight and shed infectious virus, confirming that a single intranasal dose of cb1 eliminates mucosal shedding and confers sterilizing mucosal immunity sufficient to halt SARS-CoV-2 transmission in a hamster model.
“The vaccine’s ability to block transmission is a game-changer. By inducing strong mucosal immunity in the respiratory tract, this vaccine has the potential to both protect individuals and cut chains of transmission in the community, which is crucial for controlling future outbreaks and pandemics,” commented Professor Malik Peiris of the School of Public Health at HKU.