A new engineered glycated vaccine induced production of neutralizing antibodies against severe acute respiratory coronavirus 2 (SARS-CoV-2) and other coronaviruses in mice, scientists at The University of Osaka and the RIKEN Center for Integrative Medical Science (CIMS) in Yokohama have reported.
If this new vaccination strategy can be successfully translated into humans, it could lead to the development of a next-generation vaccine capable of preventing future coronavirus pandemics, which represent a significant threat to global health, the authors predicted in the Oct. 8, 2021, issue of the Journal of Experimental Medicine.
"Previous coronavirus epidemics have occurred due to zoonotic coronaviruses crossing the species barrier, so the future emergence of similar viruses is potentially a significant threat to global public health, despite effective vaccines for current viruses," said study leader Tomohiro Kurosaki.
The SARS-CoV-2 virus responsible for the ongoing COVID-19 crisis, which is thought to have originated in bats, enters and infects human cells via a viral spike protein, which binds with human angiotensin-converting enzyme 2 (ACE2) cell surface receptors.
The SARS-CoV-2 spike protein receptor-binding domain (RBD) comprises an evolutionally conserved core region similar in all coronaviruses, with a more specialized head region mediating binding to the ACE2 receptor.
Antibodies recognizing the viral spike RBD head region can block SARS-CoV-2's entry into cells, but offer scant protection against other coronaviruses, such as the SARS-CoV-1 virus behind the 2002/3 SARS epidemic, which is thought to have originated in civet cats.
"Conversely, antibodies recognizing the spike RBD core region can prevent the entry of different coronaviruses into human cells," said Kurosaki, a professor in the WPI Immunology Frontier Research Center at Osaka University and a group leader at RIKEN CIMS.
However, "individuals exposed to the viral spike protein generally produce copious antibodies against the head region, but few if any antibodies recognizing the core region," Kurosaki told BioWorld Science.
This suggests that, although the generation of broadly neutralizing antibodies is possible, "SARS-CoV-2 infection and current vaccines are unlikely to protect against the future emergence of novel SARS-related viruses," said Kurosaki.
Therefore, in their new Journal of Experimental Medicine study, Kurosaki and his research team opted to investigate a new vaccination strategy that might enable the immune system to produce more broadly neutralizing antibodies.
They first genetically engineered the SARS-CoV-2 spike protein RBD by covering its head region in glycan molecules to shield it from the immune system, while boosting the production of antibodies against the unshielded RBD core region.
"To facilitate immune responses to the core-RBD subdomain, we introduced glycans into the CoV-2 head-RBD subdomain," explained Kurosaki.
Compared with wild-type controls, mice immunized with these engineered antibodies were shown to produce a much higher proportion of antibodies recognizing the core region of the spike protein RBD.
"Mice immunized with the engineered protein not only produced approximately 5-fold more antibodies, but also had a significantly higher affinity for the core region of the spike protein RBD," Kurosaki said.
Importantly, these antibodies were demonstrated to be capable of neutralizing the cellular entry of not only SARS-CoV-2 but also SARS-CoV-1 and three SARS-like coronaviruses derived from bats and pangolins.
"We have shown that glycan engineering onto the RBD facilitates the elicitation of potent cross-neutralizing antibodies toward [SARS-like coronaviruses, suggesting] that glycan engineering could provide a promising design for SARS-related virus vaccines," noted Kurosaki.
"These findings could therefore be useful for developing broadly protective, next-generation vaccines to prevent future coronavirus pandemics."
However, extensive further research work will be necessary in order to translate this novel vaccination strategy into humans "and to test whether our new approach is safe and effective in the human immune system," said Kurosaki.
In the meantime, "we are now trying to identify the most broadly neutralizing monoclonal antibodies that recognize the core subdomain of RBD in SARS-CoV-2-infected patients and in vaccinated persons, then we will design engineered antigens that specifically induce such antibodies."