SARS-CoV-2 receptor-binding domain-based protein subunit vaccine shows promise against multiple SARS-CoV-2 variants

In a recent study posted to the medRxiv* pre-print server, researchers described a novel protein subunit vaccine comprising the receptor-binding domain (RBD) of ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein, dimerized with an immunoglobulin (Ig)G1-fraction, crystallizable (Fc) domain.

Study: Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine. Image Credit: PIC SNIPE/Shutterstock
Study: Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine. Image Credit: PIC SNIPE/Shutterstock

Background

Due to the highly infectious and immune-evasive nature of SARS-CoV-2 and the continuous emergence of its variants, the world will require ongoing efforts to develop novel coronavirus disease 2019 (COVID-19) vaccines tailored to SARS-CoV-2 variants of concern (VOCs). Perhaps the greatest hurdle to redirecting the immune responses to VOCs is the phenomenon of immunological imprinting, also referred to as original antigenic sin. It was the first recognized problem for influenza infection and vaccination.

Immunological imprinting restricts the boosting effect of S-based booster vaccines incorporating VOC-specific S protein sequences. Since the immune system preferentially targets shared epitopes between the mutant S vaccine and the ancestral strain, this decimates the effect of all the currently used approved COVID-19 vaccines aligned towards it.

While an RBD-based protein subunit vaccine cannot completely overcome the imprinting problem, it could limit distracting the immune system to S epitopes harbored outside the RBD. Moreover, all the RBD epitopes, whether VOC-specific or shared with the ancestral strain, are more likely to induce neutralizing antibodies (nAbs). Over 90% of anti-SARS-CoV-2 nAbs target the SARS-CoV-2 RBD, the small region in its S protein that facilitates binding to host cell receptor angiotensin-converting enzyme-2 (ACE-2).

About the study

In the present study, researchers generated a vaccine candidate using SARS-CoV-2 RBD and an Fc fusion protein for facilitating multimeric presentation to the immune system. Additionally, this protein subunit vaccine engaged Fc receptor (FcR)+ antigen-presenting cells (APCs) for enhanced immunological priming. They tested its multiple formulations having different adjuvants, viz., toll-receptor 2 (TLR2) agonist R4-di-palmitoyl-S-glycerol cysteine (Pam2Cys), a natural killer T (NKT) cell agonist glycolipid alpha-galactosylceramide, and MF59® oil-in-water emulsion adjuvant. Notably, the team engineered this vaccine by fusing the N334-P527 region of the RBD to the core hinge region of mouse IgG1 via a short serine/glycine linker. They confirmed the activity of the engineered vaccine candidate by demonstrating that it specifically bound ACE2-transduced HEK-293T cell lines but not HEK-293T cells transduced with an irrelevant protein (control).

The researchers vaccinated groups of  BALB/c mice with this vaccine via subcutaneous or intranasal routes; next, they measured the elicited nAb titers using an in vitro SARS-CoV-2 micro-neutralization (MN) assay and by a surrogate virus neutralizing test (sVNT). Further, they used a microbead-based assay to determine whether sera from the immunized mice showed neutralizing activity against a broad range of SARS-CoV-2 RBD variants. Furthermore, the researchers challenged immunized mice with VIC2089 and harvested their lungs and nasal turbinates three days post-infection (dpi).

They also developed and clinically tested a ‘Beta variant’ version of their RBD  human IgG1-Fc vaccine, combined with MF59® adjuvant. Further, the team tested the ability of this modified version of the vaccine as a heterologous booster in mice previously vaccinated with two doses of a SARS-CoV-2 S protein vaccine. In this way, they evaluated its efficacy in real-world community settings, where most individuals are vaccinated with S-based vaccines.

Study findings

In the mouse model of COVID-19, each formulation of the RBD-Fc vaccine drove strong nAb responses and conferred durable and highly protective immunity against lower and upper airway infection regardless of the route of administration, but only when used in the presence of adjuvant. The vaccine adjuvanted with R4-Pam2Cys or a-GalCer adjuvant was highly effective, especially following intranasal administration. It also conferred complete protection to mice's lungs. Moreover, the immune protection was durable, as mice were challenged 75 days after the booster dose.

Notably, the Beta RBD-Fc vaccine, when used as a booster following priming with an ancestral (WT) strain S vaccine, resulted in higher mean antibody levels, including nAb, compared to a booster dose of WT, or a Beta variant, S vaccine. It also elicited cross-reactive nAbs against Alpha, Gamma, Delta, Delta+, Lambda, Mu, and Omicron BA.1 and BA.2 sublineages. It was most effective at a low dosage of one to 10 micrograms (µg). If a similar dosage remains optimal for humans, this candidate vaccine could be manufactured on a mass scale. Furthermore, stability studies showed that this vaccine was stable for up to nine months at 2-8 °C and two weeks at 37°C. This implies it will be highly amenable to transportation and storage in countries lacking cold chain infrastructure.

Conclusions

Overall, the n RBD-Fc protein subunit vaccine candidate described in the current study conferred complete and persistent protection against lower and upper airway infection in mice. Its Beta-variant version promoted potent nAb responses that targeted the beta and several other SARS-CoV-2 VOCs in in vitro MN assays and mice models. It also emerged as a suitable candidate for commercialization. It is in phase I clinical trial as a fourth dose boost for individuals primed and boosted with licensed SARS-CoV-2 vaccines.

*Important notice

medRxiv 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.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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