Abstract
Live attenuated vaccines, known as the first generation of vaccines, such as the vaccinia vaccine against smallpox, did not include an adjuvant; however, live attenuated vaccines still provide the strongest immune responses among all types of vaccines. This is because this type of vaccine contains more than just the protective antigens; they contain other, “live” materials that may enhance the immune effect elicited by the protective antigens.
Similarly, for inactivated vaccines, known as the second generation of vaccines, the use of adjuvant is not typical; however, the immunogenicity of these vaccines can be quite poor. Inclusion of an adjuvant in the vaccine formulation can greatly improve the protective immune responses, as was found for the inactivated influenza vaccines prepared recently in anticipation of an avian pandemic flu.
When the subunit or recombinant protein-based third-generation vaccines were developed, it was clear that an adjuvant must be included, such as for the highly effective hepatitis B virus (HBV) and human papillomavirus (HPV) vaccines.
The newest generation of vaccines, known as gene-based vaccines and including DNA vaccines and viral vector-based vaccines, delivers protective antigens in the form of genes, which in turn express the coded antigenic proteins in vivo to elicit a protective immune response. At first, scientists focused on the molecular aspects of gene-based vaccines in order to maximize their antigen expression. Later studies suggested that the addition of an adjuvant is also effective in further boosting the immune responses elicited by gene-based vaccines.
However, unlike the inactivated or subunit vaccines, which deliver antigens directly, an adjuvant for gene-based vaccines can also be delivered in the form of a gene and mixed with the gene-based vaccine in a final clinical formulation without much concern regarding the chemical interactions that may occur between the vaccine and the adjuvant.
Gene-based adjuvants, developed along with gene-based vaccines in the last decade, have preferentially included genes that encode proteins with known immunological stimulatory effects, such as cytokines. David Weiner's group at the University of Pennsylvania (Philadelphia, PA) has studied many such gene-based adjuvants to further improve the immunogenicity of DNA vaccines against a wide range of pathogens. As shown in a paper included in this issue of Human Gene Therapy (Kraynyak et al., 2009), one of the highly effective gene-based adjuvants discovered by this group is interleukin (IL)-15, a cytokine. In this report, they also included another gene construct that expresses a subunit of the IL-15 receptor (IL-15Rα) with the hope that an IL-5 ligand-receptor pair may be more effective in enhancing the immune responses elicited by a DNA vaccine than the ligand alone. Indeed, the DNA vaccine formulation plus the combined IL-15 and IL-15Rα genes generated higher immune responses than that using only the IL-15 gene alone. To everyone's surprise, adding the IL-15Rα gene alone also had a significant adjuvant effect when compared with the DNA formulation without any adjuvant.
This unexpected result indicating that the IL-15 receptor gene can function as an adjuvant, even independently of the IL-15 gene, opens many opportunities for future research on novel adjuvants. There has been renewed interest in adjuvants because of the finding that many traditional adjuvants can actually activate specific Toll-like receptors (TLRs) (Guy, 2007). Suddenly, the mechanisms by which adjuvants have been used empirically in the past are being revealed. However, most of these traditional adjuvants are either chemical compounds or other macromolecules, such as nucleic acids and lipopolysaccharides. Protein-based agents represent only the minority of adjuvants. The use of gene-based adjuvants has broadened the spectrum of available adjuvants, but so far gene-based adjuvants have relied mainly on known, immunologically active proteins with well-established functional pathways. Although the current paper does not answer how IL-15Rα works as an adjuvant, this study does provide evidence of the potential for using a gene-based delivery approach to identify and understand the usefulness of many cellular proteins that may have an undiscovered adjuvant effect. Compared with the approach using purified recombinant proteins, gene delivery is more efficient, less costly, and resembles more closely the in vivo expression conditions. In this sense, gene-based adjuvants, along with gene-based vaccines, are becoming new members of the ever-expanding gene therapy family.