Vaccines come in various forms, including whole organisms, partially purified components (proteins and polysaccharides), and recombinant protein-, peptide- and nucleic acid-based subunits. Vaccines consisting of whole organisms, either live-attenuated or killed by inactivation, contain nucleic acids. Such vaccines have been effectively used to prevent infectious diseases for more than two centuries since the introduction of the smallpox vaccine, which is based on a live, replicating bovine pathogen. This vaccine and others like it confer protective immunity against disease by delivery of an intact viral genome that mimics a localized infection but are safe for use in humans. Today, there are many live-attenuated vaccines licensed for humans, such as those that protect against polio, measles, mumps, rubella, influenza, yellow fever, rotavirus, chicken pox, tuberculosis and typhoid fever. However, it is not always possible or practical to utilize this approach, due to technical limitations in manufacturing or potential safety risks due to the chance of reversion to virulence of highly lethal pathogens. For these reasons, vector-based systems are being developed as a potentially safer alternative to live-attenuated vaccines.
Bacterial and viral vectors can efficiently deliver nucleic acids into cells, similar to live-attenuated, whole organism-based vaccines. However, vectors typically do not launch a live infection, as the genomes are engineered in various ways to render the vectors incapable of replicating and spreading in the immunized host. In addition, virulence factors responsible for pathogenicity are deleted or mutated rendering the vaccines safe, but in situ expression of the antigen target(s) of the vaccine is maintained. Certain vector systems have been widely used as a platform technology to deliver a variety of vaccine antigens and have been shown in many human clinical trials to be effective for induction of antigen-specific antibody and T cell responses. The most commonly used vectors are based on adenoviruses and pox viruses. However, anti-vector immunity induced by previous exposure to live infection (e.g., adenovirus) or by prior immunization (e.g., smallpox) poses a significant limitation of this approach. Anti-vector immunity, either from neutralizing antibody responses directed toward the viral proteins present on the surface of the vector or T cell responses against an expressed protein of the vector can limit effectiveness. The use of non-viral systems to deliver nucleic acids provides a means to obviate this limitation.
Plasmid DNA vaccines have been under development for more than 20 years and the general utility of the technology as a platform for induction of antibody- and T cell-mediated protection in animal models of infectious and non-infectious diseases has been widely demonstrated. Attributes of this approach include simplicity, safety, induction of broad-based immunity and lack of interference by anti-vector immunity, as shown in several hundred human clinical trials conducted to date. However, DNA vaccines have shown insufficient potency in humans despite intensive development efforts. It is believed that one of the key barriers to DNA vaccine effectiveness is inefficient delivery into cells and the nucleus, thereby limiting production of antigen in situ. Various formulations and delivery devices have been evaluated, with electroporation being among the most effective and showing promise in human clinical trials.
RNA-based vaccines were initially evaluated in animal models during the early 1990s, along with plasmid DNA vaccines. Direct injection of both mRNA and plasmid DNA into skeletal muscle of a mouse resulted in expression of the encoded protein and induction of immune responses. However, at the time, the development of a vaccine consisting of mRNA was not considered feasible due to uncertainties around RNA instability and large-scale manufacturing. As a result, DNA became the focus of nucleic acid vaccine research and development for the subsequent two decades. Technological advancements in RNA biology and chemistry during that time, however, have largely eliminated these barriers to the widespread implementation of the RNA technology.
As will be discussed in detail in this issue dedicated to RNA-based vaccines and therapeutics, the RNA technology has the potential to combine many positive attributes, making it a unique type of pharmaceutical product. These characteristics include:
Induction of both humoral and cell-mediated immunity, as with live-attenuated vaccines.
Focused immune responses, as achieved by subunit vaccines.
Safety, simplicity and lack of anti-vector immunity, as for plasmid DNA vaccines.
Localized, short-term, self-limiting in situ production of antigen or therapeutic protein.
Potential for regulated and tunable control over RNA function and gene expression.
Amenable to delivery by cell-based, viral and non-viral technologies.
Robust, generic production methods.
Rapid manufacturing, potentially within days from access to genome sequence information.
RNA is increasingly being recognized as both a pharmaceutical product as well as a drug target. The considerable experience with siRNA to modulate gene expression has laid the foundation for the development of RNA delivery technologies, robust manufacturing methods and detailed characterization of the RNA drug product. However, widespread success of siRNA has yet to be achieved in humans, in part due to the need for high levels of efficiency in gene targeting. The feasibility of using RNA as a vaccine or transcript therapy, on the other hand, seems much more achievable due to the lack of need to target many cells to exert biological effects. Vaccine use, in particular, has the advantage of the profound amplifying effects of the immune system, requiring only the appropriate trigger to set in motion a cascade of events leading to an effective host response. Indeed, vaccines based on mRNA have demonstrated proof of concept in humans and are progressing toward late-stage clinical development for cancer indications. Hence, the prospects for RNA-based vaccines and therapies are very bright and the next 5 years should bring success with first-generation products, and new technologies will drive the progression of more effective second-generation products into human clinical trials.
Financial & competing interests disclosure
Authors are employees and shareholders of Novartis Vaccines Inc. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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Notes on contributors
Andrew J Geall
