The speed of development of the COVID-19 vaccine is unprecedented, with six of them already approved for emergency use. One of the most pervasive is ChAdOx1 nCoV-19 (AZD1222) from the University of Oxford and AstraZeneca, which contains a replication-deficient adenoviral vector from a chimpanzee with the SARS-CoV-2 surface glycoprotein antigen sequence. However, the virus rapidly accumulated mutations within the receptor binding domain (RBD) and the N-terminal domain (NTD) of the spike glycoprotein, which are two primary targets of the vaccine-induced antibody response against SARS-CoV-2. . Line B.1.1.7 (or N501Y.V1), initially identified in the UK, includes the N501Y mutation linked to the increased affinity of the virus to the ACE2 receptor, but also to the increase in transmissibility of up to 53%. Furthermore, lineage B.1.351 (N501Y.V2), originally found in South Africa, bears three RBD mutations and five additional NTD mutations.
This is definitely a problem, as studies have shown that 48% of the serum samples from convalescent donors who were infected with the prototype virus were unable to neutralize this mutated strain, as determined by a spike pseudovirus neutralization test. The results of a double-blind, randomized, multisite placebo-controlled study conducted in South Africa show that the Oxford vaccine ChAdOx1 nCoV-19 (AZD1222) has no efficacy against variant B.1.351 in the prevention of mild coronavirus disease. to moderate 2019 (COVID-19) and shows reduced neutralization properties of the developed antibodies. The findings are published in the New England Journal of Medicine. The main exclusion criteria were the presence of HIV, previous or current COVID-19, a history of vaccine-related anaphylaxis and morbid obesity. The selected participants were aged between 18 and 65 years.
They were assigned to receive two doses of vaccine (in a 1: 1 ratio) containing 5 × 10 to 10 viral particles or placebo (saline or 0.9% sodium chloride) 21-35 days apart. After the second dose, serum samples were collected from 25 participants and subsequently tested with live virus and pseudovirus neutralization tests against the original D614G virus strain and variant B.1.351. Safety and efficacy against symptomatic and laboratory-established COVID-19 were the primary goals. In addition, the University of Oxford was responsible for overseeing the entire process. In this interim report, both live virus and pseudovirus neutralization tests demonstrated greater resistance to variant B.1.351 in serum samples from vaccinated subjects than in placebo-treated subjects. Mild to moderate COVID-19 was observed in 3.2% of placebo recipients and 2.5% of vaccinated subjects, representing an efficacy of 21.9%.
However, both neutralization experiments provide evidence of reduced or repudiated vaccine-induced antibody neutralization against variant B.1.351, similar to the responses observed in vaccinated participants in research activities conducted in Brazil and the United Kingdom. A potential solution has come forward against such a problem: that of administering circular RNA vaccines. The messenger RNA (mRNA) vaccines currently approved by Moderna and Pfizer-BioNTech were developed before the variants emerged, so information is limited. The Johnson & Johnson single injection vaccine was effective against the original strain in Wuhan, China, and variant B.1.1.7 was first reported in South London last fall. Variant B.1.351 was initially discovered in South Africa and may escape the immune system. New preclinical research from the University of Milan has proposed the development of a circular RNA vaccine against the variants.
Their results showed that the circular RNA vaccine creates neutralizing antibodies and strong T cell responses against the receptor binding domain of the spike protein. The circular RNA vaccine also effectively neutralized the mutated receptor binding domain found in variant B.1.351. The findings could help manage variant B.1351 and other disturbing variants. The team used a group I ribozymes autocatalysis strategy to produce circular RNA-coding antigens specific to the SARS-CoV-2 receptor binding domain (circRNARBD). Their circular RNA pattern proved to be more resistant against RNAase R than linear RNA. When purified circRNARBD was inserted into HEK293T cells, they found many antigens – 50 times more than linear RNARBD groups specific for the SARS-CoV-2 receptor binding domain. These antigens prevented a SARS-CoV-2 pseudovirus infection and also showed high thermal stability.
When stored at room temperature prior to cell transfection, circRNARBD continued to show expression two weeks after storage. Then the experiments with mice began. Mice were injected intramuscularly with 10 μg or 50 μg of the experimental circRNARBD vaccine at a two-week interval. Immunity was measured two to five weeks after the recall. Titers of immunoglobulin G (IgG) and antibodies were expressed in a dose-dependent manner and persisted two and five weeks after booster. It also effectively neutralized a SARS-CoV-2 pseudovirus. The researchers suggest that the vaccine creates a lasting immune response against SARS-CoV-2. When assessing immune responses of CD4 + and CD8 + T cells after vaccination, the researchers found Th1 lymphocytes that produced interferon-γ (IFN-γ), tumor necrosis factor (TNF-α) and interleukin-2 (IL-2). ).
Circular RNA vaccines stimulated a Th1 but not Th2 immune response. Several CD8 + cytokine-producing mice were also detected in mice vaccinated with circRNARBD. Interestingly, the team also found more robust immune responses in CD4 + and CD8 + effector memory T cells at 10 μg compared to 50 μg. However, 50 μg induced greater potency of neutralizing antibodies in B cell responses. The team collected serum from immunized mice 1 and 2 weeks after the booster shot. They found specific IgG titers for the spike protein receptor binding domain with the 501.YV2 mutation. The researchers then evaluated the neutralizing activity of the mice with the circRNARBD or circRNARBD-501Y.V2 vaccines against the D614G, B.1.1.7 / 501Y.V1, or B.1.351 / 501Y.V2 variants. Antibodies from the circRNARBD vaccine effectively neutralized all three viral strains with the highest activity against the D614G strain. In contrast, circRNARBD-501Y.V2 also neutralized all strains, with the highest neutralization activity against the corresponding variant, 501Y.V2.
These preliminary data are still in the validation phase and do not appear in any official scientific journal. But they give hope that there is an alternative against the limitations of the first vaccines developed. Incidentally, the vaccine from the Chinese company CanSino is based on ciRNA technology, is under clinical study and under analysis by the competent authorities for commercial approval.
- Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.
Madhi SA et al. New Engl J Med 2021 Mar 16.
Arora S, Singh P et al. Gene. 2020; 762: 145057.
Weisshoff H et al. Heliyon. 2020; 6 (11): e05421.
Dott. Gianfrancesco Cormaci
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