Enhancing tumor specific immune responses by transcutaneous vaccination.

Our understanding of the involvement of the immune system in cancer control has increased over recent years. However, the development of cancer vaccines intended to reverse tumor-induced immune tolerance remains slow as most current vaccine candidates exhibit limited clinical efficacy. The skin is particularly rich with multiple subsets of dendritic cells (DCs) that are involved to varying degrees in the induction of robust immune responses. Transcutaneous administration of cancer vaccines may therefore harness the immune potential of these DCs, however, this approach is hampered by the impermeability of the stratum corneum. Innovative vaccine formulations including various nanoparticles, such as liposomes, are therefore needed to properly deliver cancer vaccine components to skin DCs. Areas covered: The recent insights into skin DC subsets and their functional specialization, the potential of nanoparticle-based vaccines in transcutaneous cancer vaccination and, finally, the most relevant clinical trial advances in liposomal and in cutaneous cancer vaccines will be discussed. Expert commentary: To define the optimal conditions for mounting protective skin DC-induced anti-tumor immune responses, investigation of the cellular and molecular interplay that controls tumor progression should be pursued in parallel with clinical development. The resulting knowledge will then be translated into improved cancer vaccines that better target the most appropriate immune players.journal articlereviewresearch support, non-u.s. gov't2017 11importe

Evaluating Human Immune Responses for Vaccine Development in a Novel Human Spleen Cell-Engrafted NOD-SCID-IL2rγNull Mouse Model

The lack of preclinical models able to faithfully predict the immune responses which are later obtained in the clinic is a major hurdle for vaccines development as it increases markedly the delays and the costs required to perform clinical studies. We developed and evaluated the relevance to human immune responses of a novel humanized mouse model, humanized-spleen cells-NOD-SCID-gamma null (Hu-SPL-NSG), in which we grafted human spleen cells in immunodeficient NOD-SCID-IL-2rγnull (NSG) mice. We selected the malaria vaccine candidate, Liver Stage Antigen 3-Full Length, because we had previously observed a major discrepancy between preclinical and clinical results, and compared its immunogenicity with that of a shorter form of the molecule, LSA3-729. NSG mice engrafted with human spleen lymphocytes were immunized with either LSA3-FL or LSA3-729, both adjuvanted with montanide ISA720. We found that the shorter LSA3-729 triggered the production of human antibodies and a T-helper-type 1 cellular immune response associated with protection whereas LSA3-FL did not. Results were consistent in five groups receiving lymphocytes from five distinct human donors. We identified antigenic regions in the full-length molecule, but not in the shorter version, which induced T-regulatory type of cellular responses. These regions had failed to be predicted by previous preclinical experiments in a wide range of animal models, including primates. Results were reproducible using spleen cells from all five human donors. The findings in the Hu-SPL-NSG model were similar to the results obtained using LSA3-FL in the clinic and hence could have been used to predict them. The model does not present graft versus host reaction, low survival of engrafted B lymphocytes and difficulty to raise primary immune responses, all limitations previously reported in humanized immune-compromised mice. Results also point to the shorter construct, LSA3-729 as a more efficient vaccine candidate. In summary, our findings indicate that the Hu-SPL-NSG model could be a relevant and cost-saving choice for early selection of vaccine candidates before clinical development, and deserves being further evaluated

A Serine Protease Homolog Negatively Regulates TEP1 Consumption in Systemic Infections of the Malaria Vector Anopheles gambiae

Clip domain serine protease homologs are widely distributed in insect genomes and play important roles in regulating insect immune responses, yet their exact functions remain poorly understood. Here, we show that CLIPA2, a clip domain serine protease homolog of Anopheles gambiae, regulates the consumption of the mosquito complement-like protein TEP1 during systemic bacterial infections. We provide evidence that CLIPA2 localizes to microbial surfaces in a TEP1-dependent manner whereby it negatively regulates the activity of a putative TEP1 convertase, which converts the full-length TEP1-F form into active TEP1(cut). CLIPA2 silencing triggers an exacerbated TEP1-mediated response that significantly enhances mosquito resistance to infections with a broad class of microorganisms including Plasmodium berghei, Escherichia coli and the entomopathogenic fungus Beauveria bassiana. We also provide further evidence for the existence of a functional link between TEP1 and activation of hemolymph prophenoloxidase during systemic infections. Interestingly, the enhanced TEP1-mediated immune response in CLIPA2 knockdown mosquitoes correlated with a significant reduction in fecundity, corroborating the existence of a trade-off between immunity and reproduction. In sum, CLIPA2 is an integral regulatory component of the mosquito complement-like pathway which functions to prevent an overwhelming response by the host in response to systemic infections

Antigen-Specific IgG Responses from Naive Human Splenocytes: In Vitro Priming Followed by Antigen Boost in the SCID Mouse

AbstractHigh titers of Ag-specific human IgG were consistently achieved in SCID mice reconstituted with human splenocytes that had been primed with Ag in vitro and then boosted with Ag after engraftment into SCID mice. Specific human IgG titers in the hu-SPL-SCID mice reached approximately 1:4 × 105 when the mice were immunized with a neo-antigen, whereas titers reached 1:2 × 106 when recall responses were induced. Booster immunizations with Ag 21 days after the initial in vivo boost further enhanced this response, and specific human IgG titers of 1:17 × 106 were achieved. This represented an essentially monospecific IgG population. These responses were CD4+ T cell dependent. In addition, affinity maturation of the human Ab responses was observed. Spleens of hu-SPL-SCID mice with Ag-specific titers ≤1:1 × 106 were often significantly enlarged and often displayed visible tumors. Fourteen of sixteen B cell tumors removed from spleens of five such hu-SPL-SCID mice, produced Abs that were specific for the immunizing Ags. From such tumor, cloned cell lines were established. One such mAb, MLN-7 (γ1,κ), was raised to tetanus toxoid and had no identified cross-reactivity.</jats:p

Protection of medical and paramedical university students in Lebanon against measles, mumps, rubella and varicella: Active measures are needed

SummaryObjective: In many countries, universities require students to either show a physician-certified proof of immunity or to get vaccinated against measles, mumps, rubella and varicella, prior to their registration in medical and paramedical majors. The objective of this study was to evaluate the need to implement this policy in Lebanon. Design: A cross-sectional study was performed on students of the Lebanese University (LU), faculties of Medicine, Dentistry, Pharmacy and Public Health. Methods: The serological immunity status was assessed by determining specific antibody titer and the disease and vaccination history of 502 students was collected. Based on percentages of susceptibility, a cost-effectiveness analysis was performed to compare systematic vaccination without prior serological testing with selective vaccination of seronegative students. Results: Percentages of individuals with serologically confirmed immunity against varicella, measles, rubella and mumps were 93%, 86%, 88% and 75% respectively, and 42% of the students were susceptible to at least one of the pathogens covered by the MMR vaccine. Compilation of 186 vaccination records indicated that only 19 students (10%) had been adequately vaccinated. Moreover, among those, 7 students (37%) were still unprotected against at least one virus. Systematic vaccination against MMR was found to be 4–5 times less expensive than selective vaccination, while selective vaccination of seronegative individuals was more cost-efficient for varicella. Conclusion: Since, in this population, very few individuals were able to present a proof of adequate vaccination, it is recommended to systematically vaccinate healthcare students in Lebanon against MMR. For varicella, selective vaccination after serological testing should be performed

<it>Aedes albopictus</it> in Lebanon, a potential risk of arboviruses outbreak

Abstract Background The mosquito Aedes albopictus is undergoing a worldwide expansion with potential consequences on transmission of various arboviruses. This species has been first detected in Lebanon in 2003. Methods We performed a phylogenetic study of Lebanese specimens and assessed their host preference by detecting human, cat, dog and chicken immunoglobulins in mosquito blood-meals. Their capacity to transmit arboviruses was investigated by providing infectious blood-meals using an artificial feeding system followed by detection of viral particles in mosquito saliva. Results Our results suggest that Lebanese strains are part of the recent wave of Ae. albopictus expansion and are related to some European, African and North American strains. They exhibited a host preference towards humans and an important capacity to transmit arboviruses. Indeed, we showed that Ae. albopictus was able to transmit chikungunya (CHIKV), dengue (DENV) and West-Nile (WNV) viruses. At day 10 after an infectious blood-meal at a titer of 108 MID50/ml, 30% of mosquitoes delivered an average of 515 ± 781 viral particles of CHIKV in saliva collected using a forced salivation technique and 55% with an average of 245 ± 304 viral particles when infected with WNV. Whereas DENV was not found in saliva at day 10 post-infection (pi), an average of 174 ± 455 viral particles was detected in 38.1% of mosquitoes tested at day 21 after an infectious blood-meal at a higher titer of 109 MID50/ml. Conclusion These observations suggest that Ae. albopictus around Beirut is a potential vector of the three tested arboviruses.</p