Background – This workshop was motivated by BNext’s interest in technologies that facilitate timely response to infectious disease outbreaks through the rapid design and manufacture of vaccines against newly emergent pathogens. A compelling technology for rapid response to an ongoing outbreak is nucleic acid-based vaccines. Nucleic acid-based vaccines are attractive for rapid response because, in theory, DNA or RNA antigens that provoke a protective immune response could be quickly and inexpensively designed, manufactured, and used speedily in the clinic. Big pharma and biotech companies are interested in advancing nucleic acid-based vaccines. Several candidates are in clinical trials, though no nucleic acid-based vaccines have achieved FDA approval. Among the hurdles associated with DNA or RNA based vaccines are the following:
All Available Cellular Delivery Technologies Have Limitations – Major techniques to deliver the nucleic acid “payload” inside cells have been demonstrated – including electroporation, viral vectors and a variety of lipid nanocarriers – but all are problematic. Electroporation is suitable only for laboratory settings and not feasible in a mass casualty setting. Viral vectors carry the risk of unintentional immune reactions, and the virus carrier can only deliver certain types of payloads. Lipid nanocarriers are arguably the most advanced modality and are the delivery vehicle used in seven of eight ongoing RNA vaccine trials and in gene therapy trials. But they too are disadvantaged by the relatively “fragile” supply chain that is being used primarily for other products.
Manufacturing viruses and lipids is itself a hurdle to be overcome, especially if vaccine were needed in large quantities. For example, the supply chain capacity for GMP-grade lipids is limited, and currently being stretched by demand for the second-generation Shingles vaccine.
Similarly, manufacture of GMP-grade nucleic acid at scale is not currently possible at speed and would probably require 12 months. Making DNA in the U.S. Government’s Advanced Development Manufacturing Facilities may make this possible in 6 months. Several biotech companies are working hard to improve de novo DNA synthesis, but we are not yet able to do this at the required scale and time frame. DARPA is starting a program to develop novel approaches for DNA manufacturing at scale too.
Regulatory approval of novel cellular delivery methods requires a time-consuming and costly investment of resources, a fact that creates a rational disincentive to innovate. Nonetheless, successful and safe cellular delivery is a central feature of many of the most promising new drugs, including gene therapies. The commercial stakes involved in these new approaches will likely advance the science of cellular delivery, hopefully to the benefit of nucleic acid-based vaccines.
Conclusions: Advances in delivery modalities other than the current mainstays – existing viral vectors, lipid nanocarriers – should be supported. Supporting alternative DNA synthesis technologies and nimble, efficient biomanufacturing capabilities should be a priority.