Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen. Three emergent SARS-like diseases caused by zoonotic betacoronaviruses have caused serious outbreaks in the last two decades. Even as vaccines are administered globally to minimize the infection and severity of the disease, the emergence of circulating variants of concern (VOC) has raised concerns for sustained vaccine efficacy.

The receptor-binding domain (RBD) of the virus’s spike protein engages the primary host cell receptor, angiotensin-converting enzyme 2 (ACE2), for both SARS-CoV-2 and SARS-CoV-1. It is a promising domain for vaccine-elicited immune responses. Potently neutralizing monoclonal antibodies isolated against SARS-CoV-2 are also found to target the RBD.

Studies have demonstrated the potential for RBD-based vaccines (co-formulated with adjuvants) being efficacious against SARS-CoV-2 variants and other coronavirus species. To address the many challenges to control current pandemic and future outbreaks, a team of researchers in the U.S. has developed a highly efficient and broad-spectrum vaccine.

In a recent bioRxiv* preprint, the large team of researchers evaluated a SARS-CoV-2 Spike receptor-binding domain ferritin nanoparticle protein vaccine (RFN) in a nonhuman primate challenge model. This study addresses the need for a next-generation, efficacious vaccine with an increased pan-SARS breadth of coverage.

The researchers showed that the RFN, adjuvanted with a liposomal-QS21 formulation (ALFQ), elicits humoral and cellular immune responses exceeding those of current vaccines in terms of breadth and potency and protects against high-dose respiratory tract challenge.

This study showed that immunization with the RFN induces robust and broad antibody and T cell responses, as well as protection against viral replication and lung pathology following high-dose respiratory tract challenge in the nonhuman primate model, rhesus macaques.

They also reported that the neutralization activity against the B.1.351 VOC within two-fold of the wild-type virus and SARS-CoV-1 indicated exceptional breadth.

Our findings demonstrate RBD-specific immunity elicited by a condensed two-dose vaccine regimen is protective and, importantly, cross-neutralizes the more resistant B.1.351 variant.”

The ferritin nanoparticles and the ALFQ were evaluated for vaccination against multiple pathogens in humans in phase 1 clinical trials. The researchers designed a SARS-CoV-2 RBD ferritin nanoparticle vaccine (RFN) as a ferritin-fusion recombinant protein that self-assembles into a 24-mer nanoparticle displaying a multivalent ordered array of RBD on its surface.

Although the researchers used a rigorous challenge model in which viral loads of the control animals exceeded that of published macaque studies, the replicating virus was rapidly cleared in the airways of vaccinated animals.

Additionally, the researchers also developed a similar ferritin nanoparticle immunogen displaying the full prefusion stabilized SARS-CoV-2 spike glycoprotein (SpFN) and reported its immunogenicity and efficacy in non-human primates. While the RFN elicited similar or better responses, the researchers pointed out that the overall magnitude of these differences was small. This suggests that both the RBD and S proteins are similarly immunogenic and protective when complexed to ferritin nanoparticles and administered with ALFQ adjuvant at these vaccine doses.

However, S-based immunogens may offer the advantage of broadening the specificity of the immune response to other domains and subdomains of the spike protein, limiting the potential for viral escape."

Based on the immunologic, virologic, and pathologic assessments of the immunized primates, the researchers concluded that the candidate RFN vaccine adjuvanted with ALFQ elicited robust and broad humoral and T cell responses and protection from high-dose respiratory tract challenge, in rhesus macaques.

Interestingly, the researchers demonstrated the binding, neutralizing, and effector antibody responses in all animals – with comparable or greater magnitude to that observed in the pre-clinical studies of EUA (emergency use authorized) vaccines. This study presents a broad, potent and efficacious immunity elicited by RFN-ALFQ. The researchers discussed the present vaccine candidates and the comparative efficacy of RFN-ALFQ.

They determined that the immunogenicity and efficacy of ALFQ-adjuvanted RFN compare favorably to the pre-clinical macaque data reported for the three COVID-19 vaccines authorized for emergency use.

The researchers shared that further work is ongoing to elucidate the potential mechanisms of cross-protective responses in this study, including epitope mapping of the antibody binding responses.

For sustained vaccine efficiency, the vaccines must also be effective against the emergence of circulating variants of concern (VOC). The results in this study support consideration of RFN for any SARS-like betacoronavirus vaccine development, 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.