Evaluation of the efficacy of needle-free intradermal immunizaion of DNA vectors and recombinant proteins: implications for optimization of the needle-free technology

Abstract

Vaccination is an important contribution of medical sciences to the society. Smallpox has been eradicated and polio is on the verge of eradication owing to successful vaccines and vaccination programs. Many dreadful diseases such as yellow fever, measles, diphtheria, and meningitis were successfully controlled by vaccination. The traditional vaccines, however, met with limited success in controlling chronic infections such as HIV-1, the Plasmodium parasites, Mycobacterium tuberculosis, and the like, that collectively account for over four million deaths a year. The failure mandates novel vaccination strategies. The rational vaccine design aims to develop vaccines using a prior knowledge of the infection and the immune response. A crucial factor that determines the efficacy of immunization is the route of administration. Currently, most vaccines are administered intramuscularly. The intradermal (ID) route can be a superior alternative to the traditional intramuscular (IM) or subcutaneous (SC) administration. A variety of professional antigen-presenting cells (APC) residing in the skin tissue can make the ID a superior route of immunization. Of the several different types of APC, the dendritic cells (DC) of the skin are of special interest due to their functional heterogeneity. The delivery of vaccines through the ID route can target diverse dermal DC subsets resulting in a distinct and desirable immune response, thereby enhancing the immunogenicity of vaccines. Furthermore, ID immunization demonstrated a dose-sparing effect in the case of a few vaccines. A significant gap exists in our understanding of the response of the various skin DC subsets to different types of vaccines and formulations. A barrier to understanding the dermal DC subsets is the difficulty associated with administering antigens in the ultra-thin layers of the skin which historically limited a wider application of ID immunization. In clinical practice, the Bacillus Calmette-Guerin (BCG) vaccine is the only prophylactic vaccine currently being delivered through the ID route. The ID immunization using the needle and syringe assembly is not a preferred strategy of vaccination for technical reasons including the difficulties involved in delivering larger volumes, and the occurrence of excessive inflammatory reactions at the site of injection due to the presence of adjuvants in the formulation. Moreover, the needle-syringe-mediated ID strategy does not lend itself for a mass vaccination program unlike the recent advances in the needle-free (NF) technology. Performing an ID immunization with an NF device is reliable, reproducible, and does not require substantial technical expertise. In addition to simplifying the procedure of immunization, the NF devices improve the safety profile of the vaccination and enhance the immunogenicity of various vaccines. The NF-technology also offers a means to investigate the potential of the diverse dermal DC subsets in a small animal model such as mouse. The studies presented in this thesis are an effort towards this long-term goal.