The Next Generation of DNA Vaccines Is Poised to Transform the Healthcare Landscape

By Teri Heiland 

October 13, 2014 | Contributed Commentary | Over the last several decades, the advent of biotechnology has enabled a brand new class of “third generation” vaccines, including nucleic acid (DNA and RNA) vaccines. These nucleic acid vaccines deliver a DNA or RNA sequence into tissue, where the cells that take up the sequence synthesize the encoded protein within the cell.  The result is an antigen protein, derived from the viruses, bacteria, parasites, or tumors targeted by the vaccine, which offers protective immunity from the pathogenic agent from which the DNA or RNA was derived.1 

Nucleic acid vaccines have the potential to change the vaccination landscape through easier, more scalable, less expensive and logistically simpler vaccines that better prevent infectious disease.  What’s more, immunotherapies are being developed to treat and mitigate diseases that have never before been addressed in this way, including allergies, cancer and autoimmune disorders. Previously, technical challenges have stood as obstacles to safely administering these vaccines while delivering a strong level of effectiveness.

In recent years, however, new technologies are emerging that may help DNA vaccines achieve greater efficacy and meet their true potential. Delivery devices like electroporation and needle-free jet injectors aim to increase the amount of gene transfer into the cells, attempting to achieve higher antigen expression.

For example, the Biojector-2000 (B2000) and Biojector ID Pen by Bioject Medical Technologies, Inc., are needle-free jet injection systems intended to deliver vaccines intramuscularly, subcutaneously and intradermally. The belief is that delivery to particular parts of the body can focus the delivery of DNA to chosen cell types.  In the case of DNA plasmids delivered intradermally by the Bioject devices, vaccines are directly presented to antigen presenting cells. Some researchers believe these delivery advances correlate to improved humeral and cellular immunity in humans and animals.

The Impact of Biotechnology 

In addition to novel delivery methods, there have been real advances in plasmid backbone and antigen design. Optimal vector design, aided by bioinformatics systems, includes elements that enhance antigen expression and duration, including codon optimization, and can direct antigen presentation to particular parts of the immune system by combining the key nucleic acid antigen sequence with an immunomodulatory sequence. Modern vector design can also address regulatory concerns about antibiotic selection markers by using non-coding RNA selection markers, all while improving manufacturing yield and quantity using advanced plasmid manufacturing methods.2 

At ITI, we are working with Lysosomal Associated Membrane Protein (LAMP), a glycoprotein found on the lysosomal membrane, as the preferred immunomodulatory sequence included in all of our DNA vaccines. LAMP is used as a nucleic acid coding sequence which diverts the synthesized protein products of DNA and RNA-based vaccines to the lysosome in antigen-presenting cells, stimulating helper T cells, which leads to production of antibodies and Th1 cytokines, while also activating CD8+ cytotoxic T cells. Other third generation vaccines companies are pursuing other strategies to direct antigens to key cell structures in the immune system. For instance, Immune Design makes vaccines that use a synthetic molecule, Glucopyranosyl Lipid A, to direct tumor antigens to the TLR4 receptors of dendritic cells in the skin.

The way that nucleic acid vaccines are being used in the context of different vaccination regimens has also advanced, as researchers are now more aware of optimal dosing, timing, and ways to combine nucleic acid vaccines with other elements, such as adjuvants or peptides. One leading approach, the “prime-boost” methodology, involves “priming” or vaccinating first with a DNA vaccine, which is believed to activate antigen specific memory T cells and, in some cases, in turn activate antigen specific B cells.  “Boosting,” or following with a recombinant protein or peptide-based vaccination, re-exposes the immune system to the antigen in a different form, as a protein. Circulating antigen-presenting cells can take up this protein and travel to the lymph nodes or spleen where they elicit the activation of these memory cells and B cells, resulting in a stronger immune response. Such methodologies have been pioneered by thought leaders in DNA vaccines, including Dr. Shan Lu, M.D., Ph.D., of the University of Massachusetts Medical School.3 

With these new advances and techniques, DNA vaccines are currently under development for infectious disease, cancer, autoimmune and allergy indications and are now closer than ever to entering clinical use.

Recent Successes in Nucleic Acid Vaccines 

The industry is showing renewed interest in DNA and RNA nucleic acid vaccines through strategic alliances forged between Roche/Inovio and Sanofi/Curevac, as well as positive clinical trial results, including encouraging Phase II data in HPV by Inovio Pharmaceuticals.4 

DNA and RNA vaccines have also shown some success in cancer immunotherapies. In contrast to chemotherapy regimens often associated with severe side effects, cancer immunotherapy stimulates the body’s immune system and natural resistance to cancer. This year, Boehringer Ingelheim will pay mRNA drug developer CureVac $45 million for an RNA vaccine in early clinical development to treat lung cancer, paving the way for up to $556 million in future payments. Meanwhile, Inovio is developing a technology platform to discover and develop “synthetic” DNA vaccines, and has partnered with Roche on several candidates.

Use of these therapies in the clinic continues to grow, as the market for cancer immunotherapies alone is expected to reach over $9 billion by 2020. Nucleic acid vaccination has the potential to play a large part in this.

Next Steps for Nucleic Acid Vaccines 

Even with this progress, there are still barriers and misconceptions to overcome. These include long-held impressions about poor human immunogenicity, and concerns among European and Asian regulators over safety issues related to DNA vaccine integration into the host genome — in stark contrast to the regulatory authorities in the US, who have already issued affirmative statements regarding the safety of DNA vaccines.

It is the job of nucleic acid vaccine companies and the scientific community to engage with the appropriate regulatory authorities, and lead working groups to overcome these misgivings.  Unfortunately, there appears to be a shrinking group of DNA and RNA vaccine scientists and less collaboration across technologies, at a time when an increased exchange of ideas regarding design, assays, and combinations of technology can greatly enhance their success. Therefore, researchers working in DNA and RNA vaccines and surrounding technologies must band together and collaborate to ensure that the outside world has knowledge of the key advances, progress and potential of this groundbreaking class of new vaccines.

Dr. Teri Heiland is currently the Vice President of Research and Development at ITI. She is an experienced molecular biologist and holds multiple patents in the field of genomics. Prior to ITI, Dr. Heiland led multiple research teams at Capital Genomix, Inc. developing and validating GeneSystem320 and applying this technology to identify biomarkers associated with cancer. Prior to joining Capital Genomix, Dr. Heiland worked as a senior scientist in R&D at Kirkegaard & Perry Labs (KPL) where she spent four years as a project leader.

1 “DNA Vaccines: A Review,” Liu, MA, 2003: Journal of Internal Medicine. Accessed on Pubmed: 

2 “Improving DNA Vaccine Performance Through Vector Design,” Williams, J, 2014: Current Gene Therapy. Accessed on Pubmed: 

3 “Heterologous Prime-Boost Vaccination,” Lu, Shan, 2009: Current Opinion in Immunology. Accessed on PMC: 

4 Inovio presentation PDF: 



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