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Numerous vaccines based on different platforms are developed against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic.

The SARS-CoV-2 genome encodes four structural proteins—spike (S), membrane (M), envelope (E), and nucleocapsid (N). The S protein binds to the angiotensin-converting enzyme (ACE) receptor on the host cell through its receptor-binding domain (RBD). The RBD is considered the main target antigen for vaccines against SARS-CoV-2.

Study: Immunization with RBD-P2 and N protects against SARS-CoV-2 in nonhuman primates. Image Credit: Numstocker / Shutterstock

A recent study published in the journal Science Advances, fexofenadine 10mg explores the immunization of RBD with the P2 epitope of tetanus toxoid, to enhance its immunogenicity, and also tests the benefit of N protein in the vaccine.

An interdisciplinary team from South Korea developed a previously unidentified SARS-CoV-2 subunit vaccine (RBD-P2) by fusing the P2 epitope of tetanus toxoid with the RBD of the spike protein. And they tested the efficacy of the RBD-P2 with or without the N protein in mice, rats, and nonhuman primates (NHPs).

Consistent with the previous finding, they found higher neutralizing antibody titers against SARS-CoV-2 in rats when immunized with the RBD-P2 than that with RBD.

Additionally, with the alum as an effective adjuvant, the (RBD-P2 + alum) induced a robust neutralizing antibody response in NHPs, protecting against the SARS-CoV-2 challenge. Thus, they conclude that immunization with RBD-P2 + alum can induce effective and sufficient virus-neutralizing activity and provide protection.

However, the researchers pointed out that they could not determine the long-term humoral immunity in NHPs post-RBD-P2 + alum boost, as the primates were challenged with SARS-CoV-2 6 weeks after boosting.

While many of the vaccine candidates currently under clinical or preclinical trials involve at least a portion of the spike protein, it is still unclear whether the N protein of SARS-CoV-2 in combination would be beneficial for immunization protection against the SARS-CoV-2.

Because in vivo protection conferred by vaccines containing the N protein has not yet been experimentally validated, the researchers find out here in the comparative study of the immune responses elicited by RBD-P2 and RBD-P2/N immunization in three different animals—mice, rats, and NHPs.

The researchers found enhanced T cell-mediated immune responses and increased CD69 expression in CD4+ T cells as well as IFN-γ and IL-4 production in mice.

In the study, the NHPs immunized with RBD-P2 or RBD-P2/N were protected from the SARS-CoV-2 challenge. The researchers found increased production of IFN- γ and the numbers of IFN- γ producing cells. However, they noted that the production of TH2-type cytokines (IL-4, IL-5, and IL-13) was very low. They also observed that the RBD-P2/N + alum–immunized NHPs showed faster SARS-CoV-2 clearance than that of RBD-P2 + alum immunized NHPs in throat swab samples. “Thus, increased T cell activation and TH1-prone responses may result in faster viral clearance and constrain viral spread,” observed the researchers.

A significant point discussed in the paper is the focus of the vaccine design on S protein vs. N protein. Because of the mutations in the spike protein, many variants of the SARS-CoV-2 have emerged. Relatively, the N protein is more conserved, and hence the researchers believe that vaccines based on the N protein may provide effective protection against SARS-CoV-2 variants too.

Thus, the researchers believed that the combination of an RBD-P2/N immunization might be advantageous in overcoming escape mechanisms of SARS-CoV-2 because of gene mutations encoding the spike protein.

The researchers discussed the limitations of this study. Due to the concentrations of the RBD-P2 and the N protein used to immunize the NHPs, the effectiveness of the N protein could vary depending on the dose of RBD-P2. While they called for the need for further studies to determine the optimal dose or ratio involving the N protein, they informed that they are evaluating the RBD-P2–based subunit vaccine in clinical trials (phase 1, no. NBP2001) – because RBD-P2 and RBP-P2/N showed similar protective efficacy in NHPs.

In summary, this study demonstrates two highlights: 1) RBD-P2 + alum immunization elicits a robust neutralizing antibody response and provides complete or near-complete elimination of live SARS-CoV-2 virus particles; and 2) the potential use of the N protein provides insight into the development of SARS-CoV-2 vaccines.

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.