Immunotherapy Against HPV16/18 Generates Potent T _H 1 and Cytotoxic Cellular Immune Responses

Abstract

Despite the development of highly effective prophylactic vaccines against human papillomavirus (HPV) serotypes 16 and 18, prevention of cervical dysplasia and cancer in women infected with high-risk HPV serotypes remains an unmet medical need. We report encouraging phase 1 safety, tolerability, and immunogenicity results for a therapeutic HPV16/18 candidate vaccine, VGX-3100, delivered by in vivo electroporation (EP). Eighteen women previously treated for cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) received a three-dose (intramuscular) regimen of highly engineered plasmid DNA encoding HPV16 and HPV18 E6/E7 antigens followed by EP in a dose escalation study (0.3, 1, and 3 mg per plasmid). Immunization was well tolerated with reports of mild injection site reactions and no study-related serious or grade 3 and 4 adverse events. No dose-limiting toxicity was noted, and pain was assessed by visual analog scale, with average scores decreasing from 6.2/10 to 1.4 within 10 min. Average peak interferon-g enzyme-linked immunospot magnitudes were highest in the 3 mg cohort in comparison to the 0.3 and 1 mg cohorts, suggesting a trend toward a dose effect. Flow cytometric analysis revealed the induction of HPV-specific CD8+ T cells that efficiently loaded granzyme B and perforin and exhibited full cytolytic functionality in all cohorts. These data indicate that VGX-3100 is capable of driving robust immune responses to antigens from high-risk HPV serotypes and could contribute to elimination of HPV-infected cells and subsequent regression of the dysplastic process.

Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose

“…In addition, cell-based production necessitates extensive purification steps, hampering efforts to respond to outbreaks rapidly. DNA-based vectors used for genebased vaccination (18)(19)(20) have shown efficacy in humans (21), but raise safety concerns due to the risk of mutagenic integration into the patient's genome (22,23). Nonretroviral RNA vaccines are attractive due to their inherent transience and absence of recombination or integration into the patient's genome.…”

Multivalent TB vaccines targeting the esx gene family generate potent and broad cell-mediated immune responses superior to BCG

“…We have recently reported that highly optimized DNA vaccination with adaptive electroporation (EP) can elicit a strong Th1 and CD8 T cells, cellular immunity necessary to prevent diseae after exposure with Mtb, 28,[35][36][37][38][39] thus suggesting it as a promising platform for the development of a TB vaccine. Although a few studies have shown that EP can enhance immune responses to a DNA TB vaccine, [40][41][42] no current studies have tested this improved optimized DNA platform in the TB animal model.…”

The Road Ahead for Cervical Cancer Prevention and Control

“…For example, if a second generation of hpv vaccines that extend protection to other hr-hpv types comes to market, policymakers might once again need to readjust screening guidelines 76 , reinforcing the need for an innovative risk-assessment strategy that is flexible with respect to the growth of the new technologies 42 . Recently, ground-breaking discoveries have also occurred in the field of hpv microbicides and therapeutic vaccines research that might once again transform the landscape of cervical cancer prevention and control strategies to include novel treatment options for hpv and associated malignancies [76][77][78] . Since introduction of the first clinical hpv tests roughly 20 years ago, the field of hpv research has experienced tremendous growth (reflected by a 400% increase in the annual number of articles on papillomavirus in Medline's PubMed database over that time period) marked by all the key events outlined here and ultimately capped with a Nobel prize to Dr. zur Hausen in 2008 for his pioneering role in establishing hpv as the main causal agent in cervical cancer 75 .…”