A new set of strategies to combat coronavirus disease 2019 (COVID-19) is being investigated, as well as other future viral pandemics. This includes the use of new antigens, adjuvants, and delivery systems.
A new study in the journal MedComm describes the potential use of circular ribonucleic acid (circRNA) vaccines against COVID-19.
Study: Circular RNA vaccine, a new mRNA vaccine design strategy for SARS-Cov-2 and variants. Image credit: Christoph Burgstedt / Shutterstock.com
Introduction
The COVID-19 pandemic was caused by severe acute respiratory syndrome (SARS-CoV-2) coronavirus 2, which enters the host cell through the use of its viral spike antigen. To this end, the receptor binding domain (RBD) within the SARS-CoV-2 ear protein binds to the host cell angiotensin 2 converting enzyme (ACE2) receptor.
The devastating nature of the COVID-19 pandemic spurred global research efforts, culminating in the production and emergency authorization of several COVID-19 vaccines within a year of the outbreak. .
Some of the most notable COVID-19 vaccines included those built on the messenger ribonucleic acid (mRNA) platform. These vaccines were found to induce efficient neutralizing antibodies (nAbs) and helper (Th1) type 1 cell responses, along with antiviral effector cellular responses involving CD8 + interferon γ (IFN-γ) T cells. +).
However, these vaccine platforms have some inherent defects, as they are extremely thermal and therefore require strict and costly manufacturing processes. This feature of mRNA vaccines has also presented logistical challenges for storage and transportation, making them unsuitable for low-resource environments.
MRNA vaccines present many technical challenges, especially due to their vulnerability to heat-induced denaturation and enzymatic degradation by RNase R exonuclease. Therefore, these vaccines should be manufactured in RNase-free environments and in very sterile conditions.
In addition, linear mRNA requires the addition of a 5 ‘cap and a 3’ polyadenine (polyA) tail, with modified nucleotides such as 1-methylpseudouridine (1mΨ) to ensure that digestion does not occur. of exonuclease. The use of lipid nanoparticles (LNPs) to encapsulate mRNA provided additional protection.
The design strategy and main advantages of the circRNA vaccine against SARS-CoV-2 and variants. (A and C) Compared to m1Ψ-mRNARBD, circRNARBD has a longer half-life and longer-lasting antigen expression. (B) The IRES element is introduced to initiate the translation of the SARS-CoV-2 RBD antigen. (D, F, and G) LNP-encapsulated circRNA vaccines injected intramuscularly into rhesus mice and macaques induce a higher proportion of neutralizing antibodies and Th1-bias immune response than m1Ψ-mRNA, which is more conducive to the elimination of SARS-CoV-2. (E) The CircRNARBD-Delta vaccine provides broad-spectrum protection against Delta and Omicron variants. (A), (C) and (E) were reproduced from ref. 1.
Study results
The current study describes the benefits and advantages of circRNA technology for COVID-19 vaccines. The circRNA vaccine platform was developed to try to improve the excellent efficacy of conventional mRNA vaccines in clinical treatment.
Previous research has suggested the use of the circRNA platform to express the desired antigen within an LNP envelope. Linear RNA became circular in shape, while optimizations improved in vitro transcription.
When tested in mice, the circRNA vaccine elicited elevated RBD-specific immunoglobulin G (IgG) antibody titers. This serum was found to neutralize both the pseudovirus and the wild-type strain of SARS-CoV-2 effectively, thus indicating the efficacy of the vaccine in vivo.
Subsequent research showed that circRNA was less susceptible than linear RNA vaccines over a temperature range of up to 28 days. LNP-circRNA-RBD expressed the RBD antigen at a higher level than both the unmodified spike mRNA and the optimized RNA platform containing 1mΨ, which was represented as 1mΨ-mRNARBD. The former resulted in higher IgG2a and IgG2c antibody subclasses compared to IgG1, and higher proportions indicated Th1-biased immune responses.
This promotes viral elimination, which is an important benefit of circRNA vaccines. The circRNA vaccine also demonstrated its ability to induce a higher proportion of nAbs compared to binding antibodies.
Therefore, LNP-circRNARBD may be better to elude antibody-dependent infection enhancement by virus-specific antibodies. “
Three doses of the circRNARBD-Delta vaccine resulted in a significantly protective increase in nAbs in both the SARS-CoV-2 Delta and Omicron (VOC) concern variants. This vaccine appears to provide broader protection against emerging SARS-CoV-2 VOCs; however, the circRNARBD-Omicron vaccine was not able to protect against Delta infection.
When tested in monkeys at different doses, a similar Th1-biased response was observed. When challenged with the wild-type strain of SARS-CoV-2, the viral load in these monkeys one week after infection was a thousand times lower. In addition, the lungs of vaccinated monkeys also appeared to be protected against severe COVID-19.
Conclusions
Although mRNA vaccines are highly immunogenic and can enter the host cell, while resisting the digestion of exonuclease through many modifications of the basic structure, there are several limitations associated with this vaccine platform. For example, the use of an LNP shield requires ultra-cold storage and transport conditions.
The circRNA vaccines described here produce nAb titers at a level similar to those caused by 1mΨ-modified linear RNA vaccines. However, their covalent ring structure protects them from enzymatic degradation, thus improving their stability.
CircRNA vaccines can synthesize and release antigens in vivo, while inducing Th1-biased cellular immune responses.
More research is needed to compare circRNA vaccines with the most widely used mRNA vaccines against COVID-19. Although the current study does not aim to present a vaccine ready for clinical use, its success could lead to more innovations in this field to finally allow the emergence of more effective and stable mRNA vaccines.
Magazine reference:
- Su, P., Zhang, L., Zhou, F. and Zhang, L. (2022). Circular RNA vaccine, a new mRNA vaccine design strategy for SARS-Cov-2 and variants. MedComm. doi: 10.1002 / mco2.153.