Novel linear DNA SARS-CoV-2 vaccine using electroporation-aided vaccine delivery reveals lower viral shedding in ferrets

In a recent study posted to the bioRxiv* preprint server, a team of researchers evaluated the efficacy, immunogenicity, and safety of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) linear deoxyribonucleic acid (DNA) vaccine in ferret models, delivered using intramuscular injection and electroporation.

Study: A linear SARS-CoV-2 DNA vaccine candidate reduces virus shedding in ferrets. Image Credit: Billion Photos/Shutterstock
Study: A linear SARS-CoV-2 DNA vaccine candidate reduces virus shedding in ferrets. Image Credit: Billion Photos/Shutterstock

Background

According to the World Health Organization (WHO) reports, the coronavirus disease 2019 (COVID-19) pandemic has resulted in over 600 million cases and more than 6 million deaths worldwide. Global vaccination efforts have successfully limited the severity of and mortality due to the disease.

Belonging to the genus Betacoronavirus, SARS-CoV-2 is a positive-sense, single-stranded ribonucleic acid (RNA) sarbecovirus with a surface glycoprotein or spike (S) protein that mediates viral entry into the host cell. The receptor binding domain (RBD) of the S protein binds to the angiotensin-converting enzyme 2 (ACE2) receptor on host cells. The RBD has been the target for many vaccines and monoclonal antibodies developed against SARS-CoV-2.

DNA vaccines have the advantages of being stable at room temperature and relatively inexpensive and easy to manufacture, apart from being safer than other vaccines. DNA vaccines have also induced cytotoxic (CD8+) and helper (CD4+) T cells. However, the efficacy of DNA vaccines needs to be improved, and methods such as electroporation are being explored to increase the in vivo cellular uptake of the DNA vaccine.

About the study

In the present study, the researchers designed and produced a novel vaccine consisting of linearized, codon-optimized complementary DNA (cDNA) which encoded the SARS-CoV-2 spike protein RBD.

The study was carried out on 25 12- to 16-month-old ferrets, divided into five groups, each consisting of three males and two females. The control group (G1) received sterile water injections, while the G2, G3, G4, and G5 groups received 0.25 mg primary vaccine and booster, 1 mg primary vaccine and booster, 0.25 mg single dose, and 1 mg single dose, respectively. A booster dose was administered to groups G1, G2, and G3 on day 28. Intramuscular electroporation was carried out immediately after vaccination.

Nasal, oropharyngeal, and rectal swabs and blood samples were collected after sedating the animals with dexmedetomidine. Fluorescent bead-based multiplex and viral neutralization assays were carried out to assess the serological response by measuring the levels of S protein-RBD-specific and neutralizing antibodies.

The animals from all five groups were challenged with a SARS-CoV-2 Alpha variant isolate to measure the viral efficacy. The nasal, oropharyngeal, and fecal samples were tested for SARS-CoV-2 RNA using real-time reverse transcriptase polymerase chain reaction (rRT-PCR) to understand viral replication and RNA shedding in all the animals.

Results

The results reported no major adverse reactions to the vaccine or the electroporation technique, apart from a slight increase in the body temperature the day after primary and booster vaccinations in all animals, including the control group.

All G2 animals who received 0.25 mg primary and booster vaccinations had seroconverted and exhibited the highest anti-RBD and neutralizing antibodies. Furthermore, G2 animals also displayed higher T cell responses than the control group, indicating that 0.25 mg of primary and booster vaccinations induced both cellular and humoral immune responses.

SARS-CoV-2 RNA was detected in nasal, oropharyngeal, and fecal samples of all groups from the first to the tenth day following the viral challenge. The oropharyngeal secretions had the highest viral RNA loads during the first three days after the viral challenge. The animals from G2 and G3, who received primary and booster doses, showed a significant decrease in oropharyngeal viral RNA loads only around the seventh day. Compared to G5, which received only a single 1 mg vaccine dose, G3 and G2 showed a decrease in nasal viral RNA loads by day 7 and day 10, respectively.

Animals from G2 shed no infectious SARS-CoV-2 virus after the first day of the viral challenge. Overall, nasal samples showed much lower concentrations of infectious viruses than oropharyngeal samples. All the vaccinated groups exhibited a decrease in infectious viral loads compared to the control group. Fecal samples showed comparatively lower viral RNA loads and no infectious viral loads.

Conclusions

To summarize, the intramuscular delivery of the novel linear DNA SARS-CoV-2 vaccine aided by electroporation was determined to be safe and elicited humoral and cellular immune responses. A low (0.25 mg) dose of primary and booster vaccinations induced high levels of anti-RBD and neutralizing antibodies and significantly decreased the shedding of infectious SARS-CoV-2 viruses.

The authors believe that the increased efficacy of the low doses of the linear DNA vaccine could be attributed to improved vaccine delivery enhanced by the electroporation technique.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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