Evaluation of a synthetic DNA SARS-CoV-2 vaccine INO-4800 using a nonhuman primate model

On March 13, 2020, the World Health Organization (WHO) officially declared the outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which is the virus responsible for the coronavirus disease 2019 (COVID-19), to be a global pandemic.

SARS-CoV-2 is a single-stranded ribonucleic acid (RNA) betacoronavirus that shares 95% genomic sequence similarity with SARS-CoV-1, which was a coronavirus that spread throughout many countries in 2002. Scientists around the world are working tirelessly to develop effective vaccines to contain the COVID-19 pandemic.

Previous research has indicated that the spike (S) protein is an important target for emerging vaccines, as well as therapeutics. To date, most of the COVID-19 vaccines have been designed on the basis of the entire S antigen or a truncated form that can induce host immune responses and protect the body from viral infection.

Several vaccines, which have been based on either nucleic acid or adenovirus technologies, have received emergency use authorization in many countries around the world. Vaccinating the global population will require billions of doses.

Study: One or two dose regimen of the SARS-CoV-2 synthetic DNA vaccine INO-4800 protects against respiratory tract disease burden in nonhuman primate challenge model. Image Credit: Billion Photos / Shutterstock.com

INO-4800: a synthetic DNA vaccine

INO-4800 is a codon-optimized plasmid DNA vaccine that encodes the wild-type SARS-CoV-2 S protein. Earlier in vivo studies have revealed that INO-4800 can elicit T and B cell responses against SARS-CoV-2. Scientists have found that this vaccine can also lower the viral replication upon the challenge of human angiotensin-converting enzyme 2 (ACE2)-transduced mice.

Similarly, inoculation of INO-4800 in the rhesus macaque SARS-CoV-2 challenge model had shown induction of immunological memory cells which could lower the viral replication. For the development of vaccines and therapeutics, the nonhuman primates (NHP) model is extremely valuable, as these animals can be infected with SARS-CoV-2 and develop symptoms similar to human beings with mild COVID-19.

How effective is INO-4800?

The Phase I clinical trial of the INO-4800 vaccine has demonstrated its safety and tolerability profile. In fact, this vaccine-elicited immune responses in 100% of the recipients and has been found to protect these individuals by inducing both SARS-CoV-2 neutralizing antibodies as well as cellular immune responses.

Currently, the INO-4800 vaccine is undergoing further evaluation in a Phase 2 segment of a Phase 2/3 study. The main aim of this clinical trial is to further evaluate the safety, immunogenicity, and efficacy of the vaccine.

A new study published in Vaccine assesses the safety and efficacy of the synthetic DNA vaccine candidate INO-4800, delivered as a single or double dose regime. This vaccine was administered in the skin of the rhesus macaque using CELLECTRA-ID electroporation technology.

In this study, 12 rhesus macaques, including 6 males and 6 females, were vaccinated with the INO-4800 vaccine. One group received one dose of the vaccine injected on day 28, while the second group received one dose of the vaccine on day 0 and a second dose on day 28. The serum titers of SARS-CoV-2 S antigen reactive immunoglobulin G (IgG) antibodies were measured in all animals biweekly between days 0 and 56. The scientists reported that this vaccine triggered a functional T cell response, as SARS-CoV-2 S protein neutralizing antibodies boosted after the second dose.

Humoral responses in rhesus macaques vaccinated with INO-4800. Study outline (A). SARS-CoV-2 Spike-specific IgG (B), RBD-specific IgG (C) and live virus-neutralising antibodies (D) measured pre- and post-challenge in serum from rhesus macaques that received 1 or 2 doses of INO-4800 or were unvaccinated (Control). Lines represent the geometric means.

The efficacy of INO-4800 after SARS-CoV-2 challenge

The vaccinated animals were then challenged with a high dose of SARS-CoV-2 Victoria01 strain (5X106 pfu) on the 56th day of their vaccination to assess the effectiveness of the vaccine.

No significant clinical symptoms were observed throughout the study. Nasal and throat samples were collected to measure the viral RNA and subgenomic RNA (sgmRNA) content via the reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) assay. This analysis revealed a significant negative correlation between nasal viral loads and neutralizing and anti-receptor binding domain (RBD) IgG titers on day 3, but not on day 1.

At the time of necropsy, researchers collected bronchoalveolar lavage (BAL) fluid from each animal. Analysis of these samples showed an overall reduction in the levels of SARS-CoV-2 viral RNA and sgmRNA in the vaccinated group. However, their levels varied depending on the day of necropsy.

RT-qPCR was also carried out on tissues collected at necropsy. This analysis revealed that in most of the tissues, except the lungs, the RNA levels of SARS-CoV-2 were below the limit of quantification. Estimation of the viral load in the lung tissues showed reduced viral load in the vaccinated animals.

Taken together, the RT-qPCR viral load data revealed a positive effect in reducing viral loads among the INO-4800 vaccinated rhesus macaques, even after being challenged with a high dose of SARS-CoV-2. Further, histopathological examination of lung tissue provided no indication of vaccine-enhanced disease in the vaccinated animals that were subjected to high virus load.


The authors of this study have conducted preclinical SARS-CoV-2 animal model studies to assess the INO-4800 vaccine. Their assessment reveals that a single dose of the vaccine has a positive impact on lowering the viral load in the lungs and no vaccine-enhanced disease was found.

As synthetic DNA vaccines can be developed at a faster rate than conventional vaccines, they could play an important role in containing the ongoing COVID-19 pandemic.

Journal reference:
Dr. Priyom Bose

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.


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