Could DNA Vaccines Be Reaching Their Prime?

In his talk at the 15th Annual Conference on Vaccine Research about advances in vaccine discovery, David Weiner, chair of the gene therapy and vaccines program at the University of Pennsylvania, recalled that it has been about two decades since the “public coming out” of DNA-based vaccination in AIDS research. 

The pivotal event was a 1992 meeting in Cold Spring Harbor that showcased findings from a trio of papers and many researchers hoped the approach, which essentially involves joining fragments of HIV’s genetic material to harmless pieces of bacterial DNA called plasmids to form a vaccine, would revolutionize AIDS vaccine development. But while the strategy was safe and effective, the DNA vaccine candidates were weakly immunogenic due to poor DNA uptake into cells. Scientists experimented using DNA vaccines as a prime followed by a boost, but the results were still underwhelming.

While these suboptimal immune responses were a big disappointment for the field—Weiner described it as a DNA vaccine hangover and even had cartoons to illustrate his point—he said a more sober field has made considerable progress in making DNA candidates more competitive.

For instance, Weiner said codon optimization has improved protein expression of the genes by as much as 50%. They have also employed adjuvants to boost the immune response and began delivering the vaccine candidates via electroporation.

Recent findings from animal and clinical studies are encouraging. Weiner’s lab, which has been collaborating with the company Inovio Pharmaceuticals to test three DNA vaccine candidates for AIDS, recently concluded a Phase 1 trial of 48 adults in the US that found T cell responses from one of those candidates—PENNVAX-B targeting HIV Gag, Pol and Env proteins from a clade B strain—were highest among a menu of HIV vaccine candidates, including those employing adenovirus virus and modified Vaccinia Ankara viral vectors. In the PENNVAX-B study, three doses of the vaccine were delivered along with an IL-12 plasmid adjuvant using electroporation.  The study found that 89% of the vaccinated recipients mounted T cell responses against at least one of the antigens.

Weiner said the same PENNVAX-B regimen in nonhuman primates, but with a different electroporation configuration, was able to elicit antibody responses that neutralized sensitive tier 1 viruses. He added that he and his colleagues are now trying to direct the immune responses to “sites where it matters” by co-delivering cutaneous T cell attracting chemokine (CTACK) and mucosa-associated epithelial chemokine (MEC) proteins as adjuvants.