Nucleic acid-based Vaccines: New Kids on the Block and Hope for SARS-CoV-2

There have been several eras of vaccine approaches, each with successful outcomes in preventing or decreasing severity of disease. Traditionally, vaccines have utilized live but weakened, or attenuated viruses and others have used killed, or inactivated viruses. Newer approaches have engineered viruses as vectors to deliver a selected gene of the pathogen of interest to induce immune memory. Most recent to the scene are the use of nucleic acids which, like viral vector vaccines, deliver a selected gene of the pathogen to induce immune memory. While there have been many nucleic acid vaccine candidates that have started clinical trials and shown promise, none have been approved to date. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, may usher in a new vaccine era with the first approved nucleic acid-based vaccine.

The two arms of the nucleic acid-based vaccines are DNA and nucleoside modified messenger RNA (mRNA). Upon injection, cells uptake the nucleic acid and use it to produce an antigen, or a molecule that can trigger an immune response. Through various mechanisms, the antigen induces a pathogen specific immune memory which serve to mount rapid, pathogen-specific immunity upon subsequent exposures to the pathogen.

A major advantage of nucleic acid vaccines over traditional approaches is the ease of manufacturing. Because the production of nucleic acid vaccines does not require cell culture, animal products, or the safety precautions needed for propagating virus, they are a well-suited approach for rapid response. These manufacturing advantages decrease production costs and allow more efficient large-scale production in shorter timeframes whichare highly attractive in the fight against an epidemic like SARS-CoV-2.

Image: Vaccination platforms DNA, mRNA and traditional. (Click to enlarge)


  • A T cell is a type of lymphocyte that plays a central role in the immune response. T cells, also known as killer cells, are cytotoxic – this means that they are able to directly kill virus-infected cells.
  • An antibody is a large Y-shaped protein that is used by the immune system to neutralize pathogens, such as bacteria and viruses. Antibodies may stop a biological process or activate macrophages to destroy.

One of the major differences between DNA and mRNA vaccines is the type of immune response elicited. DNA vaccines trigger a more T cell heavy response which limits the spread of the pathogen by cytotoxic immune cells killing infected cells. Modified mRNA vaccines trigger a more B cell heavy response whereby antibodies limit infection by clearing extracellular pathogens. It is currently unknown what level of these responses correlates to protection against SARS-CoV-2, so it is unclear which nucleic acid vaccine platform is more suitable.

In terms of DNA vaccines for SARS-CoV-2, Inovio Pharmaceuticals’ INO-4800 candidate is currently in Phase 1 clinical trials. INO-4800 delivers the gene for the SARS-CoV-2 spike protein, which is a protein that interacts with human cells for viral entry. Inovio’s previous codevelopment and success in early stages of clinical trials for a DNA vaccine for the spike protein of another coronavirus, Middle Eastern Respiratory Syndrome (MERS-CoV), has guided their current vaccine design. The months to come will shed light on the DNA vaccine design strategy for these two coronaviruses as clinical trial data is collected.

There are two candidates currently in clinical trials for SARS-CoV-2. Moderna and the National Institute of Allergy and Infectious Diseases (NIAID) have partnered to make the vaccine candidate mRNA-1273. Their vaccine was granted Fast Track designation by the FDA to expedite studies, so as it continues gathering Phase 1 clinical data, it can simultaneously proceed with Phase 2. Like Inovio, Moderna and NIAID also made a mRNA vaccine for the spike protein of MERS-CoV. Exact differences between the Inovio and Moderna-NIAID vaccine candidates are unclear, since details on vaccine design are unpublished. In addition to design differences, due to the different nucleic acid approaches between the two companies, there will inevitably be differences in which immune cells predominate the elicited immune response.

In a different mRNA vaccine approach, BioNTech and Pfizer’s program, BNT162, have Phases 1 and 2 underway. The BNT162 program has 4 different candidates: two of the molecules are for the spike protein and two are just the receptor binding domain, which is the portion of the spike protein that binds with the human cell receptor during viral entry. One of the constructs is a self-amplifying mRNA which has enhanced, but delayed production of antigen. By combining more than one construct especially with the self-amplifying mRNA, the final BNT162 vaccine may increase the overall immune memory.

The global race to a safe, effective vaccine will continue in the coming months. There are currently eight vaccine candidates in clinical trials, and three of them, described here, are nucleic acid-based vaccines. This epidemic marks many historical firsts and may also be a first for an approved nucleic acid-based vaccine.


Claire-Anne Siegrist. “Vaccine Immunology.” Plotkin’s Vaccines 7: 16-34 (2018).

Inovio. “DNA Medicines Pipeline” (2020).

Jon Cohen. “Scientists are moving at record speed to create new coronavirus vaccines—but they may come too late.” Science Magazine News (Jan 2020).

Jon Cohen. “With record-setting speed, vaccinemakers take their first shots at the new coronavirus.” Science Magazine News (Mar 2020).

Moderna. “Moderna Receives FDA Fast Track Designation for mRNA Vaccine (mRNA-1273) Against Novel Coronavirus.” (May 2020).

Victoria Rees. “A Phase I/II clinical trial for BioNTech’s BNT162 vaccine programme to prevent COVID-19 infection has been granted approval in Germany.” European Pharmaceutical Review Apr 2020).

WHO. “Draft landscape of COVID-19 candidate vaccines.” (May 2020).

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