A recent study published in the Science journal depicted that mosaic receptor-binding domain (RBD) nanoparticles immunize from diverse sarbecovirus challenges, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), among animal models.
This infographic illustrates the new vaccine, composed of RBDs from eight different viruses. The table shows the broad spectrum of SARS-CoV-2 variants and related coronaviruses that the vaccine induces protection against. Credit: Courtesy of Wellcome Leap, Caltech, and Merkin Institute
In the last 20 years, epidemics or pandemics associated with SARS-CoV and SARS-CoV-2, two animal CoVs from the sarbecovirus lineage, have affected the human species. Despite the swift development of potent vaccines, the CoV disease 2019 (COVID-19) pandemic induced by SARS-CoV-2 has been enduring for more than two years globally. Indeed, the novel SARS-CoV-2 variants of concern (VOCs), such as the severely mutated Omicron VOCs, have protracted the COVID-19 pandemic.
Additionally, the finding of different sarbecoviruses in bats, some of which engage the angiotensin-converting enzyme 2 (ACE2), the entry receptor for SARS-CoV and SARS-CoV-2, increases the risk of a new CoV pandemic. Therefore, the development of therapeutics and vaccines to guard against both zoonotic sarbecoviruses and SARS-CoV-2 VOCs is urgently needed.
The study's authors previously categorized SARS-CoV-2 neutralizing anti-RBD antibodies into four primary classes (class I, II, III, and IV) according to their epitopes and whether they identified down- or up-RBDs on the spike (S) trimers. The vaccine approaches eliciting class III, class IV, and class I/IV antibodies could immunize from potentially developing zoonotic sarbecoviruses and contemporary and upcoming SARS-CoV-2 variants.
About the study
In the present research, the scientists outlined animal immunogenicity and virus challenge assessments to analyze mosaic-8 RBD-nanoparticles, a possible pan-sarbecovirus vaccine wherein RBDs from SARS-CoV-2 and seven animal sarbecoviruses were bonded covalently to a 60-mer protein nanoparticle.
The team used the SARS-CoV-2 Beta RBD for the challenge analyses. They created either mosaic-8b, i.e., each nanoparticle displaying the SARS-CoV-2 Beta RBD and seven other sarbecovirus RBDs bonded to the 60 regions, or homotypic, i.e., each nanoparticle showcasing 60 replicas of the SARS-CoV-2 Beta RBD, RBD-mi3 nanoparticles. The researchers leveraged the SpyCatcher-SpyTag platform to covalently bond RBDs to C-terminal SpyTag003 sequences to a 60-mer nanoparticle, i.e., SpyCatcher003-mi3, to obtain the two types of RBD-mi3 nanoparticles.
Mosaic-8b and homotypic SARS-2 Beta RBD-mi3 immunizations induced binding and neutralizing antibodies in K18 mice. (A) Left: Immunization schedule. K18-hACE2 mice were immunized with either 5 μg (RBD equivalents) mosaic-8b, mosaic-8 g, homotypic SARS-2 Beta, or the molar equivalent of unconjugated SpyCatcher003-mi3 nanoparticles. Right: Structural models of mosaic-8 and homotypic RBD-mi3 nanoparticles constructed using PDB 7SC1 (RBD), PDB 4MLI (SpyCatcher), and PDB 7B3Y (mi3).
The authors examined immune reactions and protection from viral infection in keratin 18-human angiotensin-converting enzyme 2 (K18-hACE2) transgenic mice to compare the effectiveness of homotypic or mosaic RBD-mi3 nanoparticle vaccinations. The four cohorts of vaccinated K18-hACE2 mice, each comprising 10 animals, were infected with SARS-CoV-2 Beta or SARS-CoV.
Four days after the challenge, the researchers collected lung and oropharyngeal swab samples from four groups of K18-hACE2 mice. The scientists assessed the amounts of infectious virus and viral ribonucleic acid (RNA) in those samples.
The team also performed homotypic and mosaic RBD-mi3 nanoparticle vaccination and challenge tests in non-human primates (NHPs) to expand the current findings to another animal model of SARS-CoV-2 and SARS-CoV infection. They then investigated if anti-RBD antibodies were produced in distinct ways by homotypic and mosaic nanoparticles.
According to the study results, animals vaccinated with homotypic SARS-CoV-2 RBD-mi3 and mosaic-8b RBD-mi3 showed protection against the SARS-CoV-2 challenge. The authors noted that mosaic-8b had only one-eighth as many SARS-CoV-2 RBDs compared to its homotypic SARS-CoV-2 equivalent. These findings imply that a mosaic RBD nanoparticle may be a COVID-19 vaccination alternative for preventing present and future SARS-CoV-2 variant infections.
Additionally, mosaic-8b nanoparticles and not homotypic SARS-CoV-2 RBD-mi3 nanoparticles safeguarded K18-hACE2 mice from mortality in response to a mismatched SARS-CoV challenge, indicating that a mosaic nanoparticle vaccine might also immunize against illness brought on by prospective mismatched zoonotic sarbecoviruses.
Although the homotypic nanoparticles did not completely protect from SARS-CoV in K18-hACE2 mice, the authors noted that viral titers in lung tissue acquired from vaccinated animals were lower versus the control animals. This inference was relevant, considering the possibility of mismatched immunity imparted by homotypic SARS-CoV-2 RBD-mi3 nanoparticle vaccination. Since only one out of four animals exhibited measurable viral concentrations in the lungs relative to four out of four in the control cohort, the scientists mentioned that some amount of protection was evident.
The current findings that a mosaic RBD safeguarded against challenges from both mismatched and matched sarbecoviruses, as opposed to homotypic SARS-CoV-2 RBD nanoparticles that fully protected only from a matched challenge, were coherent with RBD mapping investigations showing that antibodies targeting conserved RBD territories, not the immunodominant class I and class II RBD epitopes, were chiefly elicited by mosaic-8b yet not by homotypic SARS-CoV-2 RBD-mi3 nanoparticles.
Collectively, the current work compared the immune reactions in macaques and mice evoked by homotypic (just SARS-CoV-2) and mosaic-8 (SARS-CoV-2 plus seven animal sarbecoviruses) RBD-nanoparticles. The investigators found that mosaic-8 provoked significant immune reactions to mismatched viral strains, such as animal sarbecoviruses and SARS-CoV.
Homotypic SARS-CoV-2 vaccination only protected from SARS-CoV-2 challenges. On the other hand, mosaic-8 vaccination demonstrated equal neutralization of SARS-CoV-2 variants, such as Omicrons, and immunized against SARS-CoV-2 and SARS-CoV infections. Following immunization with mosaic-8, epitope mapping revealed heightened addressing of conserved epitopes.
Together, the present findings indicate that mosaic-8 RBD-nanoparticles may be able to safeguard against SARS-CoV-2 variants and any future sarbecovirus spillovers.
- Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models; Chengcheng Fan, Tiong K. Tan, Alain R. Townsend, Jesse D. Bloom, Vincent J. Munster, Pamela J. Bjorkman, Mark G. Lewis, Claudia A. Jette, Han Gao, Yu E. Lee, Greg Saturday, Anthony P. West, Leesa M. Kakutani, Priyanthi N. P. Gnanapragasam, Jonathan E. Schulz, Jennifer R. Keeffe, Tyler N. Starr, Ankur Sharma, Hanne Andersen, Allison J. Greaney, Neeltje van Doremalen, Alexander A. Cohen. Science, DOI: 10.1126/science.abq0839, https://www.science.org/doi/10.1126/science.abq0839