The etiological agent of the coronavirus disease 2019 (COVID-19) pandemic is a novel human pathogen, in the Sarbecovirus subgenus of Coronaviridae. The International Committee on Taxonomy of Viruses (ICTV) Study Group named the virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The SARS-CoV-2 infects human host cells through the attachment of the structural transmembrane spike (S) glycoprotein on the virus's surface to angiotensin-converting enzyme 2 (ACE2) receptor on the host cell, followed by fusion of the viral and host membranes.

The S protein plays a crucial role in eliciting the immune response during disease progression. It is, therefore, the primary target of neutralizing antibodies (nAbs). The immunodominant receptor-binding domain (RBD) on the S protein accounts for greater than 90% of the neutralizing activity in COVID-19 convalescent sera.

To understand the ability of SARS-CoV-2 vaccine-elicited antibodies to neutralize and protect against emerging variants (that are pathogenic) and other sarbecoviruses, a large team of researchers studied immunity by receptor-binding domain nanoparticle vaccines. They showed that a clinical-stage multivalent SARS-CoV-2 receptor-binding domain nanoparticle vaccine (SARS-CoV-2 RBD-NP) protected mice from the SARS-CoV-2-induced disease.

They observed a broadly protective immunity after a single shot of the vaccine, indicating the possibility of dose-sparing. Based on the results observed, this study provides proof of principle that the sarbecovirus RBD-NPs induce heterotypic protection and enable the advancement of broadly protective sarbecovirus vaccines to the clinic, the researchers write.

The research team’s findings have been released on the bioRxiv* preprint server.

Research into the recurrent spillover of the coronaviruses (CoVs) in humans has established that the SARS-CoV-2-, SARS-CoV- and MERS (middle east respiratory syndrome)-CoV-related coronaviruses are also detected in bats. In the future, such zoonotic transmission events may continue to occur.

These coronaviruses are cytoplasmically replicating, positive-sense, single-stranded RNA viruses.

It is established that the S protein carrying the D614G mutation increases the infectivity of the SARS-CoV-2 variant. It has become the dominant form in many geographic regions but does not significantly affect antibody-mediated neutralization.

However, some mutations enabled the virus to escape from monoclonal antibodies (mAbs) and to reduce neutralization by immune sera. To overcome this issue, the formulation of mAb cocktails as a promising strategy can neutralize a broader spectrum of the circulating SARS-CoV-2 variants.

Several variants with numerous S mutations have emerged, specifically the B.1.1.7 (in the UK), B1.351 (in South Africa), and P.1 (in Brazil) lineages.

However, some of these mutations lead to significant reductions in the neutralization potency of the specific mAbs, convalescent sera and also the Pfizer/BioNTech BNT162b2- or Moderna mRNA-1273-elicited sera.

To address these challenges, the researchers in this study generated a multivalent subunit vaccine displaying the SARS-CoV-2 RBD (RBD-NP) in a highly immunogenic array, using a computationally designed self-assembling nanoparticle. Developing such a nanoparticle immunogen that displays multiple antigenic variants of viral glycoproteins to generate broadly effective protective vaccines.

The researchers expressed and purified four proteins in which the RBDs from the S proteins of SARS-CoV-2, SARS-CoV, and the bat coronaviruses WIV1 and RaTG13. These proteins were genetically fused to the I53-50A trimer, added to the I53-50B pentamer to assemble a mosaic RBD-NP(mRBD-NP) co-displaying the four RBDs on the same nanoparticle.

The researchers reported that all of these nanoparticle immunogens formed the intended icosahedral architecture and retained native antigenicity. They employed techniques such as the sandwich biolayer interferometry, SDS-PAGE, dynamic, light scattering, electron microscopy analysis of negatively stained samples and binding assay to human ACE2 (angiotensin-converting enzyme 2). They found that these vaccine candidates were stable for at least four weeks at several temperatures except at 37°C – the highest temperature evaluated.

In this study, the researchers demonstrated that in a dose-sparing manner, the RBD-NP vaccination protected the mice against the SARS-CoV-2 challenge. They reported that the SARS-CoV-2 RBD-NP vaccination-induced neutralizing antibodies (in high titers) that target diverse antigenic sites in NHPs (non-human primates).

The researchers also observed that against a panel of variants, the SARS-CoV-2 RBD-NP elicited potent neutralizing antibody responses in the NHPs. The SARS-CoV-2 RBD-NP elicited cross-reactive sarbecovirus polyclonal Abs in the NHPs.

They also evaluated the vaccine-elicited binding and neutralizing Ab titers against SARS-CoV-2 variants and distinct sarbecoviruses, and found that they elicited cross-reactive and broadly neutralizing sarbecovirus Abs; protecting against a heterotypic challenge.

Given the large number of coronaviruses circulating in zoonotic reservoirs, the researchers argue that such vaccines could be important for preventing future pandemics.

So far, the SARS-CoV-2 alone has infected over 122.3 million lives and caused over 2.7 million deaths. In an unparalleled pace of research and development to mitigate the SARS-CoC-2 infection, effective mRNA vaccines are developed and administered across the world. Currently, over 300 vaccine projects are being developed, even as several therapeutic alternatives are under trials. The sequencing of SARS-CoV-2 clinical isolates has led to the identification of numerous mutations in the >730,000 genome sequences available to date (https://www.gisaid.org/).

The study here presented that a single immunization with the SARS-CoV-2 RBD-NP confers protection

against lethal SARS-CoV-2 challenge (in mice and NHPs), suggesting that the potent Ab responses elicited could enable dose-sparing regimens to achieve global vaccination, the researchers write.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Ramya Dwivedi

Ramya has a Ph.D. in Biotechnology from the National Chemical Laboratories (CSIR-NCL), in Pune. Her work consisted of functionalizing nanoparticles with different molecules of biological interest, studying the reaction system and establishing useful applications.