In a recent study published on the preprint server medRxiv*, researchers described a novel protein subunit vaccine that includes the receptor-binding domain (RBD) of the ancestral severe acute respiratory syndrome coronavirus 2 spike (S) protein (SARS-CoV-2). , dimerized with an immunoglobulin (Ig)G1 fraction, crystallizable domain (Fc).
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 immunoevasive nature of SARS-CoV-2 and the continuous emergence of its variants, the world will require continuous efforts to develop new vaccines against the coronavirus disease 2019 (COVID-19) adapted to the variants of the SARS-CoV-2. of concern (VOC). Perhaps the greatest obstacle to redirecting immune responses to VOCs is the phenomenon of immunological imprinting, also known as antigenic original sin. It was the first recognized problem for influenza infection and vaccination.
Immunological imprinting constrains the potentiating effect of S-based booster vaccines incorporating VOC-specific S protein sequences. Since the immune system preferentially targets epitopes shared between the mutant S vaccine and the ancestral strain, this decimates the effect of all currently approved COVID-19 vaccines in use aligned with it.
Although an RBD-based protein subunit vaccine cannot completely overcome the imprinting problem, it could limit the distraction of the immune system to S-epitopes harbored outside the RBD. Furthermore, all RBD epitopes, whether VOC-specific or shared with the ancestral strain, are more likely to induce neutralizing antibodies (nAbs). More than 90% of anti-SARS-CoV-2 nAbs target the SARS-CoV-2 RBD, the small region of its S protein that facilitates binding to the 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 to facilitate multimeric presentation to the immune system. Furthermore, this protein subunit vaccine engaged Fc receptor (FcR) + antigen-presenting cells (APCs) to enhance immunological priming. They tested their multiple formulations with different adjuvants, namely the toll-like receptor 2 (TLR2) agonist R4-di-palmitoyl-S-glycerol cysteine (Pam2Cys), a T-cell (NKT) agonist glycolipid alpha-galactosylceramide and MF59. ® oil-in-water emulsion adjuvant. In particular, the team designed this vaccine by fusing the N334-P527 region of the RBD to the central hinge region of mouse IgG1 via a short serine/glycine linker. They confirmed the activity of the designed vaccine candidate by showing that it specifically bound HEK-293T cell lines transduced with ACE2, but not HEK-293T cells transduced with an irrelevant protein (control).
The researchers vaccinated groups of BALB/c mice with this vaccine either subcutaneously or intranasally; They then measured nAb titers obtained using an in vitro SARS-CoV-2 microneutralization (MN) assay and using a surrogate virus neutralization test (sVNT). In addition, they used a microbead-based assay to determine whether sera from immunized mice showed neutralizing activity against a wide range of SARS-CoV-2 RBD variants. In addition, the researchers challenged mice immunized 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 IgG1-Fc human RBD vaccine, combined with the adjuvant MF59®. In addition, 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 effectiveness in real-world community settings, where most people are vaccinated with S-based vaccines.
Results of the study
In the mouse model of COVID-19, each RBD-Fc vaccine formulation drove strong nAb responses and conferred long-lasting and highly protective immunity against lower and upper respiratory tract infection, regardless of the route of administration. administration, but only when used in the presence of adjuvant. . The vaccine adjuvanted with R4-Pam2Cys or a-GalCer adjuvant was highly effective, especially after intranasal administration. It also conferred complete protection on the lungs of the mice. Furthermore, the immune protection was long-lasting as the mice were challenged 75 days after the booster dose.
Notably, the Beta RBD-Fc vaccine, when used as a boost after priming with an ancestral S strain (WT) vaccine, resulted in higher mean antibody levels, including nAb, compared with a booster dose of WT, or a beta variant, S. vaccinia. It also elicited cross-reacting nAbs against the Alpha, Gamma, Delta, Delta+, Lambda, Mu, and Omicron BA.1 and BA.2 sublineages. It was most effective at a low dose of one to 10 micrograms (µg). If a similar dose remains optimal for humans, this vaccine candidate could be manufactured on a large scale. In addition, 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 that it will be very susceptible to transport and storage in countries that do not have cold chain infrastructure.
Conclusions
Overall, the RBD-Fc n protein subunit vaccine candidate described in the current study conferred complete and persistent protection against lower and upper respiratory tract infection in mice. Its beta-variant version promoted potent nAb responses targeting beta and several other SARS-CoV-2 VOCs in in vitro MN assays and mouse models. It also emerged as a suitable candidate for commercialization. It is in a phase I clinical trial as a fourth dose escalation for people primed and boosted with licensed SARS-CoV-2 vaccines.
*Important news
medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behavior, or be treated as established information.