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The 2019 coronavirus disease pandemic (COVID-19) is one of only three successive epidemics caused by highly pathogenic coronaviruses. The virus responsible for COVID-19 is Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), first reported in Wuhan, China.
In the absence of effective or preventive treatments, vaccines have become the center of attention. Although more than 170 vaccines are in preclinical and approximately 60 in clinical development, very few are based on plasmid DNA technology. However, a new preprinted research paper published on the bioRxiv * The server reports the immunogenicity of a DNA vaccine candidate.
Conventional vaccines
The reported efficacy for currently deployed vaccines, including mRNA vaccines from Pfizer and Moderna, and the vector-based chimpanzee adenovirus candidate AstraZeneca, is approximately 95% for mRNA vaccines and 70% for adenovirus vaccine. , respectively, based on the efficacy of phase III.
Live attenuated and inactivated or killed viral vaccines cause antibodies. In fact, the antigen contained in the vaccine is absorbed by phagocytosis or endocytosis in the host cells to be processed via the major class I histocompatibility complex (MHC I), essentially activating the antibody-producing B cells. .
DNA vaccines
Plasmid DNA vaccine is a relatively new vaccine approach intended to generate both humoral and cell-mediated immunity. To induce cell-mediated immunity, one needs antigens that are safe but processed through the endogenous pathway, thus leading to activation of T and B cells. Activated T cells will destroy the cell infected with the virus.
Mechanism of immunity
Plasmid DNA-based vaccines introduce the genes that encode the antigens of interest. The plasmid will enter and remain in the nucleus without integrating into the host DNA. It will initiate the translation of the antigenic protein encoded in the cytoplasm of the host cell.
After vaccination, the host’s immune system then monitors for these antigens as presented by one or both of the MHC I and MHC II proteins. The type of MHC molecules determines the type of immune response that follows recognition of these antigens.
Benefits of DNA vaccines
Plasmid DNA vaccines thus generate long-term and lasting immunity against viral antigen. The production of antigens by the host cell will ensure that the protein is properly folded. The signal peptide expressed simultaneously will ensure that the antigen is transported to the cell membrane.
Antigen presenting cells (APCs) recognize viral antigen on the surface of infected cells and thereby trigger the production of antibodies, including neutralizing antibodies.
The plasmid DNA vector also contains unmethylated cytidine guanosine phosphate (CpG) motifs which serve to enhance cell-mediated immune responses as well as humoral immunity. Immunity is thus induced with a single dose.
These vaccines also continue to boost immunity over the long term and do not require adjuvants. DNA vaccines also benefit from the advantages of having simple, inexpensive and easily upgradeable manufacturing processes, with a long shelf life at room temperature. These factors facilitate the distribution of these vaccines, since maintenance of the cold chain is not necessary. These are also safe even in immunocompromised patients, compared to some live vaccines.
DNA vaccines will also avoid inducing immunity against the viral vector or the potential risk of activation of the oncogene or other safety concerns associated with viral vectors.
Study details
Previous studies have shown that DNA vaccine candidates developed against SARS and MERS, past coronavirus outbreaks, are immunogenic and protective. The present study examines the preclinical performance of a SARS-CoV-2 DNA plasmid vector encoding the viral spike protein and signal peptide IgE.
The researchers first demonstrated the ability of the ZyCoV-D vaccine to express the spike protein robustly in mammalian cells and to induce antibodies that strongly bind to the target antigen. Their results indicate long-term storage of the vaccine between 2 and 8 ° C and 25 ° C for a few months. This is essential for rapid deployment in the context of the current pandemic.
The vector used in the development of this vaccine is the vector pVAX-1, used in several previous DNA vaccines, with an excellent safety profile.
In a range of animal models, namely mice, guinea pigs and rabbits, immunized by intradermal injection at three doses (25, 100 and 500 μg), they found that vaccination was followed by production of antibodies in for two weeks after the second dose, peaking at two weeks after the third dose. IgG (immunoglobulin G) antibody levels remain detectable three months after the last dose, indicating both long-lasting immunity and a secondary anamnestic response upon re-exposure.
Neutralizing antibodies
After immunization, two tests showed a robust neutralizing response, which protected the animal against viral challenge. Future studies will be needed to determine the relevance of neutralizing antibody titers as correlates of protection, regardless of the type of vaccine used, both in animals and humans. This will allow this measurement to be calibrated during the clinical development of future vaccines.
The neutralizing antibody response indicates that the immunity thus induced will also allow viral clearance and a reduction in the severity of COVID-19.
Cell mediated immunity
Successful induction of a T cell response was also observed in mice, confirming that the vaccine activates both MHC I and MHC II pathways of antigen processing. The vaccine is loaded onto both MHC I and II molecules, from viral proteins processed in the cell and viral antigens in endosomes.
Not only is cell-mediated immunity achieved, but a balanced Th1 / Th2 response is observed, as evidenced by the high levels of IFN (interferon) -γ. This is essential to avoid the risk of vaccine-associated enhanced respiratory disease (VAERD), associated with a biased Th2 response. Conversely, a Th1 response is associated with asymptomatic and mild SARS-CoV-2 infection.
Needle-free injection system
The study also reports the effectiveness of a spring-loaded, needle-less injection system (NFIS) in the rabbit study, as it reduces costs and avoids needle stick injuries while avoiding the elimination of sharp needles. Another advantage is the use of a spring instead of an external power source. The end result is a jet of DNA that penetrates the skin to achieve uniform spread, resulting in higher uptake of DNA into skin cells.
Plasmid DNA clearance
Plasmid levels were observed to become undetectable at 14 days after injection of all tissues except the injection site, where clearance took 28 days.
Conclusion
Researchers have thus developed the ZyCoV-D vaccine candidate and demonstrated its ability to induce both humoral and cellular immunity in various animals by intradermal injection over a range of dosages.
“The immunogenicity of this DNA vaccine candidate targeting the SARS-CoV-2 S protein in an animal model supports the further clinical development of this candidate in response to the current COVID-19 pandemic situation. “
*Important Notice
bioRxiv publishes preliminary scientific reports which are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behaviors, or treated as established information.
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