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Humoral immunity developed by the DNA vaccine INO-4800 is effective against SARS-CoV-2 mutants

An international team of scientists recently revealed that antibodies produced in response to the DNA vaccine INO-4800 have recently emerged in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) such as G614, 501Y.V1 We have demonstrated that it can effectively neutralize some of the mutants that have developed. , And 501Y.V2.The study is currently available at bioRxiv* Preprint server.

Background

The Coronavirus Disease 2019 (COVID-19) vaccine, which is currently being rolled out worldwide, was developed primarily against the original strain of SARS-CoV-2 (D614). With the recent emergence of new mutants (VOCs) of concern, the planet faces new challenges in the effectiveness of existing vaccines against new viral mutants. In this regard, the growing pool of evidence suggests that spike mutations present in these VOCs can reduce neutralization. Effectiveness of Antibodies developed in response to spontaneous infection by the COVID-19 vaccine or previously circulating viral variants.

In the current study, scientists found that antibodies developed in response to the major DNA vaccine INO-4800 had G614 mutations in the UK (501Y.V1), South Africa (501Y.V2), and SARS-CoV-2. We investigated whether the body could be effectively neutralized. .. The vaccine developed by Inobioffer Matthewicals in San Diego, USA Spike protein-Code sequence of the original Wuhan strain of SARS-CoV-2 as an immunogen.

Previous studies have shown that antibodies induced by the mRNA-based COVID-19 vaccine are less effective in neutralizing VOCs in both the UK and South Africa. Similarly, serum samples from South African COVID-19 patients show a significant reduction in neutralization efficiency for South African variants.

Study design

The INO-4800 vaccine examined in this study has a good profile of safety and efficacy in humans, as observed in clinical trials. In addition, the vaccine can be stored at room temperature. This is an additional benefit associated with transporting vaccines to remote areas.

A total of eight ferrets were intramuscularly immunized with two INO-4800 vaccines at 28-day intervals to elicit an anti-SARS-CoV-2 antibody response. Serum samples were collected 35 and 42 days after vaccination to ensure sufficient antibody inversion.

Cytopathic effect (CPE) inhibition assays were performed using Vero cells to examine the virus-neutralizing effect of immunized ferret sera.

Important findings

Scientists estimated the average neutralization titer of each serum sample for the viral variants tested. The findings showed that the neutralizing titers for G614 and 501Y.V1 were comparable. However, the titers for the 501Y.V2 variant were significantly lower (4x) than the titers for the other two variants.

To carry out molecular modeling experiments, scientists have developed a fully glycosylated spike protein model of three viral variants. In addition, it contained one angiotensin converting enzyme 2 (ACE2) protein that bound to the spike receptor binding domain (RBD). Finally, they used specialized software to simulate these models in aqueous solution.

The results of molecular modeling experiments indicate that structural changes in 501Y.V2 variants are more pronounced than in 501Y.V1 variants, further justifying the lower neutralization titers observed for 501Y.V2. It became clear. Similarly, broader changes were observed in the N-terminal domain (NTD) of 501Y.V2 variants with a group of mutations containing deletions of L18F, D80A, D215G, and 242-244.

Diagram of 501Y.V1 and 501Y.V2 mutations associated with ancestral types a) Structure of glycosylated SARS CoV2 peplomer highlighting S1 monomer (blue) and relative position domain of N-terminal domain (NTD) and receptor binding ( RBD) and bound ACE2 receptor (yellow). The location of the D614G (common to all tested variants) is also highlighted. b) & c) A side-by-side comparison of 501Y.V1 and 501Y.V2 variants of RBD shows V2 variants with additional K417N and E484K mutations. d) & e) Compare NTD 501Y.V1 and 501Y.V2 variants side-by-side and show the relative positions of mutations and deletions. (Model files available in supplementary material).

Diagram of 501Y.V1 and 501Y.V2 mutations associated with ancestral types a) Structure of glycosylated SARS CoV2 peplomer highlighting S1 monomer (blue) and relative position domain of N-terminal domain (NTD) and receptor binding ( RBD) and bound ACE2 receptor (yellow). The location of the D614G (common to all tested variants) is also highlighted. b) & c) A side-by-side comparison of 501Y.V1 and 501Y.V2 variants of RBD shows V2 variants with additional K417N and E484K mutations. d) & e) Compare NTD 501Y.V1 and 501Y.V2 variants side-by-side and show the relative positions of mutations and deletions. (Model files available in supplementary material).

The N501Y mutation present in the spike RBD of the 501Y.V1 mutant has been shown to increase the binding affinity of the host cell for the ACE2 receptor. In addition to the N501Y mutation, the 501Y.V2 variant spike RBD contains two other mutations, K417N and E484K. Taken together, these mutations have been shown to increase the infectivity and anti-immunity evasion of the virus.

In addition, the NTD-observed mutations in 501Y.V2 variants are expected to affect the antigen presentation and glycosylation arrangement of peplomers. Taken together, the structural changes observed in 501Y.V2 variants justify their efficacy in reducing the ability of INO-4800-inducing antibodies to neutralize.

Significance of research

This study reveals that antibodies induced by the DNA vaccine INO-4800 can effectively neutralize the G614 and 501Y.V1 mutants of SARS-CoV-2. However, the vaccine is not equally effective against 501Y.V2 variants.

The 501Y.V2 neutralizing ability of the INO-4800 vaccine is comparable to the mRNA-based COVID-19 vaccine developed by BioNTech / Pfizer and Moderna. In contrast, the adenovirus-based vaccine developed by Oxford / AstraZeneca has been shown to be significantly less effective at neutralizing 501Y.V2.

Given these observations, scientists believe: Nucleic acidThe base COVID-19 vaccine is more effective than other vaccine types in neutralizing new VOCs.

*Important Notices

bioRxiv publishes unpeer-reviewed preliminary scientific reports and should not be considered definitive, guide clinical / health-related behaviors, or be treated as established information.

Humoral immunity developed by the DNA vaccine INO-4800 is effective against SARS-CoV-2 mutants

Source link Humoral immunity developed by the DNA vaccine INO-4800 is effective against SARS-CoV-2 mutants

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