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.

Two experiments tested whether a peak-shifted generalization gradient could be explained by the averaging of distinct gradients displayed in subgroups reporting different generalization rules. Across experiments using a causal judgment task (Experiment 1) and a fear conditioning paradigm (Experiment 2), we found a close concordance between self-reported rules and generalization gradients using a continuous stimulus dimension (hue). Both experiments also showed an overall peak-shifted gradient after differential conditioning, but not after single cue conditioning. Importantly, the peak shift could be decomposed into linear and peaked gradients when participants were divided into rule subgroups. Our results highlight the need to consider individual differences in the rules that participants derive in human generalization studies and suggest that in some situations, peak shift may be a consequence of averaging across diverse rule subgroups. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Traditional associative learning theories predict that training with feature negative (A+/AB-) contingencies leads to the feature B acquiring negative associative strength and becoming a conditioned inhibitor (i.e., prevention learning). However, feature negative training can sometimes result in negative occasion setting, where B modulates the effect of A. Other studies suggest that participants learn about configurations of cues rather than their individual elements. In this study, we administered simultaneous feature negative training to participants in an allergist causal learning task and tested whether evidence for these three types of learning (prevention, modulation, configural) could be captured via self-report in the absence of any procedural manipulation. Across two experiments, we show that only a small subset of participants endorse the prevention option, suggesting that traditional associative models that predict conditioned inhibition do not completely capture how humans learn about negative contingencies. We also show that the degree of transfer in a summation test corresponds to the implied causal structure underlying conditioned inhibition, occasion-setting, and configural learning, and that participants are only partially sensitive to explicit hints about causal structure. We conclude that feature negative training is an ambiguous causal scenario that reveals individual differences in the representation of inhibitory associations, potentially explaining the modest group-level inhibitory effects often found in humans.

DNA vaccines are being developed as a potentially safe and effective immunization platform. However, translation of DNA vaccines into a clinical setting has produced results that have fallen short of those generated in a preclinical setting. Various strategies are being developed to address this lack of potency, including improvements in delivery methods. Electroporation (EP) creates transient increases in cell membrane permeability, thus enhancing DNA uptake and leading to a more robust immune response. Here, we report on the safety and tolerability of delivering sterile saline via intramuscular (IM) or intradermal (ID) injection followed by in vivo electroporation using the CELLECTRA(®) adaptive constant current device in healthy adults from two open-label studies. Pain, as assessed by VAS, was highest immediately after EP but diminishes by about 50% within 5 min. Mean VAS scores appear to correlate with the amount of energy delivered and depth of needle insertion, especially for intramuscular EP. Mean scores did not exceed 7 out of 10 or 3 out of 10 for IM and ID EP, respectively. The majority of adverse events included mild to moderate injection site reactions that resolved within one day. No deaths or serious adverse events were reported during the course of either study. Overall, injection followed by EP with the CELLECTRA(®) device was well-tolerated and no significant safety concerns were identified. These studies support the further development of electroporation as a vaccine delivery method to enhance immunogenicity, particularly for diseases in which traditional vaccination approaches are ineffective.

Generalization of learning can arise from 2 distinct sources: failure to discriminate a novel test stimulus from the trained stimulus and active extrapolation from the trained stimulus to the test stimulus despite them being discriminable. We investigated these 2 processes in a predictive learning task by testing stimulus discriminability (identification of the trained stimulus) as well as generalization of learning (outcome expectancy). Generalization gradients were broader for expectancy than for identification, in both single cue and differential (discrimination) designs, implying a substantial extrapolation component for the most dissimilar stimuli. The shapes of the expectancy gradients were strongly determined by the training design (single cue vs. differential) and by the rules inferred by participants (similarity vs. linear). By contrast, the identification gradients were unaffected by the training design or inferred rules and were equivalent for predictive and nonpredictive stimuli. These results indicate that perceptual discriminability plays a substantial role in generalization, but it is largely unaffected by associative learning. Instead, learning appears to impact on generalization via an independent extrapolation component which involves cognitive processes such as inductive reasoning.