| Popis: |
ABSTRACT Intramuscular vaccination of mice with the naked pBI-11 DNA plasmid targeting E6 and E7 of HPV16 and HPV18 via a conventional syringe and needle generates human papillomavirus (HPV) antigen-specific CD8+ T cell-mediated immune responses and therapeutic effects against the TC-1 tumor model. However, delivery of DNA vaccines by this method is less effective in patients, likely due to poor transduction of host tissues. Needle-free biojectors show great promise for DNA vaccination because of their simplicity of administration and high patient acceptability and also, we hypothesize, because of greater efficiency of cell transduction in host tissues. Here, we compared the kinetics of transgene expression from a plasmid DNA using intramuscular injection with a conventional needle administration to intradermal or intramuscular delivery with a customized Tropis biojector. Delivery using the customized Tropis biojector leads to enhanced transgene expression compared to intramuscular needle injection. In addition, we characterized the HPV antigen-specific CD8+ T cell-mediated immune responses and anti-tumor effects generated by pBI-11 DNA vaccination by each route of administration, as well as by split-dose multi-site injection. Intradermal, but not intramuscular, vaccination with pBI-11 DNA vaccine via customized Tropis biojector enhanced HPV antigen-specific CD8+ T cell-mediated immune responses over needle injection. Intradermal, but not intramuscular, vaccination via customized needle-free Tropis biojector elicited greater HPV antigen-specific CD8+ T cell-mediated immune responses as well as anti-tumor effects compared to intramuscular injection of pBI-11 with a needle. Good manufacturing practices (GMP) grade pBI-11 DNA vaccine delivered intradermally or intramuscularly via customized Tropis biojector was well tolerated by mice. IMPORTANCE Respectively, HPV16 and HPV18 cause 50% and 20% of cervical cancer cases globally. Viral proteins E6 and E7 are obligate drivers of oncogenic transformation. We recently developed a candidate therapeutic DNA vaccine, pBI-11, that targets HPV16 and HPV18 E6 and E7. Single-site intramuscular delivery of pBI-11 via a needle elicited therapeutic anti-tumor effects in mice and is now being tested in high-risk human papillomavirus+ head and neck cancer patients (NCT05799144). Needle-free biojectors such as the Tropis device show promise due to ease of administration, high patient acceptability, and the possibility of improved delivery. For example, vaccination of patients with the ZyCoV-D DNA vaccine using the Tropis device is effective against COVID19, well tolerated, and licensed. Here we show that split-dose, multi-site administration and intradermal delivery via the Tropis biojector increase the delivery of pBI-11 DNA vaccine, enhance HPV antigen-specific CD8+ T-cell responses, and improve anti-tumor therapeutic effects, suggesting its translational potential to treat HPV16/18 infection and disease. |
