Human prophylactic vaccine adjuvants and their determinant role in new vaccine formulations

Adjuvants have been considered for a long time to be an accessory and empirical component of vaccine formulations. However, accumulating evidence of their crucial role in initiating and directing the immune response has increased our awareness of the importance of adjuvant research in the past decade. Nevertheless, the importance of adjuvants still is not fully realized by many researchers working in the vaccine field, who are involved mostly in the search for better target antigens. The choice of a proper adjuvant can be determinant for obtaining the best results for a given vaccine candidate, but it is restricted due to intellectual property and know-how issues. Consequently, in most cases the selected adjuvant continues to be the aluminum salt, which has a record of safety, but predominantly constitutes a delivery system (DS). Ideally, new strategies should combine immune potentiators (IP) and DS by mixing both compounds or by obtaining structures that contain both IP and DS. In addition, the term immune polarizer has been introduced as an essential concept in the vaccine design strategies. Here, we review the theme, with emphasis on the discussion of the few licensed new adjuvants, the need for safe mucosal adjuvants and the adjuvant/immunopotentiating activity of conjugation. A summary of toxicology and regulatory issues will also be discussed, and the Finlay Adjuvant Platform is briefly summarized

Safety and Immunogenicity of a Recombinant Plasmodium falciparum AMA1 Malaria Vaccine Adjuvanted with Alhydrogel™, Montanide ISA 720 or AS02

Contains fulltext : 71100.pdf (publisher's version ) (Open Access)BACKGROUND: Plasmodium falciparum Apical Membrane Antigen 1 (PfAMA1) is a candidate vaccine antigen expressed by merozoites and sporozoites. It plays a key role in red blood cell and hepatocyte invasion that can be blocked by antibodies. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the safety and immunogenicity of recombinant PfAMA1 in a dose-escalating, phase Ia trial. PfAMA1 FVO strain, produced in Pichia pastoris, was reconstituted at 10 microg and 50 microg doses with three different adjuvants, Alhydrogel, Montanide ISA720 and AS02 Adjuvant System. Six randomised groups of healthy male volunteers, 8-10 volunteers each, were scheduled to receive three immunisations at 4-week intervals. Safety and immunogenicity data were collected over one year. Transient pain was the predominant injection site reaction (80-100%). Induration occurred in the Montanide 50 microg group, resulting in a sterile abscess in two volunteers. Systemic adverse events occurred mainly in the AS02 groups lasting for 1-2 days. Erythema was observed in 22% of Montanide and 59% of AS02 group volunteers. After the second dose, six volunteers in the AS02 group and one in the Montanide group who reported grade 3 erythema (>50 mm) were withdrawn as they met the stopping criteria. All adverse events resolved. There were no vaccine-related serious adverse events. Humoral responses were highest in the AS02 groups. Antibodies showed activity in an in vitro growth inhibition assay up to 80%. Upon stimulation with the vaccine, peripheral mononuclear cells from all groups proliferated and secreted IFNgamma and IL-5 cytokines. CONCLUSIONS/SIGNIFICANCE: All formulations showed distinct reactogenicity profiles. All formulations with PfAMA1 were immunogenic and induced functional antibodies. TRIAL REGISTRATION: (Clinicaltrials.gov) NCT00730782

Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery

BACKGROUND: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. / METHODS: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). / RESULTS: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. / CONCLUSIONS: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.

Vernacular Mudbrick Architecture in the Dakhleh Oasis, Egypt, and the design of the Dakhleh Oasis Training and Conservation Centre

More than one third of the world's population lives in houses made of unfired earth bricks or stamped earth, materials also known as mud brick, adobe, terre crue, pisé, or rammed earth. Houses in the middle east have been made out this material for at least 10,000 years, but in many places this form of architecture is slowly being superceded by more recent building techniques using reinforced concrete and concrete blocks. This study contains a description of the remaining mud brick architecture in several villages in the Dakhleh Oasis in Egypt. It includes a brief history of mud brick, a discussion of the distinct local building techniques of the Oasis, and three architectural case studies of traditional mud brick houses in the Oasis, and it has many plans and photographs of local houses. The study was carried out as preparation for the design and construction of an archaeological working and training centre in the Dakhleh Oasis, which has been made according to the local traditions in mud brick vernacular. It is based on a field trip carried out in 1997 by Wolf Schijns (architect), Margriet Schijns (architect), Olaf E Kaper (Egyptologist) and Joris D Kila (art historian)

Correlation between contrast enhancement on intraoperative magnetic resonance imaging and histopathology in glioblastoma

Contains fulltext : 110716.pdf (publisher's version ) (Open Access

Medial lower leg perforators: An anatomical study of their distribution and characteristics

Item does not contain fulltextPURPOSE: The integument of the medial lower leg is underestimated as a donor site for local and distant reconstructions. Comprehensive knowledge of its perforator anatomy is lacking. This study aims to determine perforator location and characteristics and to compare these regarding the proximal, middle and distal third of the medial lower leg. MATERIALS AND METHODS: The medial lower leg region (MLLR) of 16 cadavers was delineated and investigated after injecting the popliteal artery with acrylic paint. Following dissection, all perforators larger than 0.3 mm were localized and mapped. Their course, source vessel, length and diameter were subsequently documented. RESULTS: Overall, 122 perforators were found, 102 (83.6%) originating from the posterior tibial artery, 16 (13.1%) from the medial sural artery and 4 (3.3%) from the anterior tibial artery. A mean of 7.6 +/- 2.4 perforators (range 4-13) per MLLR was found. Most perforators (42.6%) were localized in the distal third of the MLLR, followed by the middle (36.9%) and proximal third (20.5%). The largest and longest perforators were found in the proximal third of the MLLR (diameter 1.4 mm, length 9.1 cm), followed by the middle and distal third respectively. Of all musculocutaneous perforators, the majority (78.6%) was located in the middle third of the MLLR. Of all septocutaneous perforators, most (55.3%) were found in the distal third of the MLLR. A small number of unexpected anatomical variants were found. CONCLUSION: In each third of the MLLR different perforator characteristics were found. Knowledge of these characteristics can be used to direct the reconstructive plan. (c) 2016 Wiley Periodicals, Inc. Microsurgery 37:319-326, 2017

Human prophylactic vaccine adjuvants and their determinant role in new vaccine formulations

Adjuvants have been considered for a long time to be an accessory and empirical component of vaccine formulations. However, accumulating evidence of their crucial role in initiating and directing the immune response has increased our awareness of the importance of adjuvant research in the past decade. Nevertheless, the importance of adjuvants still is not fully realized by many researchers working in the vaccine field, who are involved mostly in the search for better target antigens. The choice of a proper adjuvant can be determinant for obtaining the best results for a given vaccine candidate, but it is restricted due to intellectual property and know-how issues. Consequently, in most cases the selected adjuvant continues to be the aluminum salt, which has a record of safety, but predominantly constitutes a delivery system (DS). Ideally, new strategies should combine immune potentiators (IP) and DS by mixing both compounds or by obtaining structures that contain both IP and DS. In addition, the term immune polarizer has been introduced as an essential concept in the vaccine design strategies. Here, we review the theme, with emphasis on the discussion of the few licensed new adjuvants, the need for safe mucosal adjuvants and the adjuvant/immunopotentiating activity of conjugation. A summary of toxicology and regulatory issues will also be discussed, and the Finlay Adjuvant Platform is briefly summarized

IFN-γ receptor-deficient mice generate antiviral Th1-characteristic cytokine profiles but altered antibody responses

The lymphokine IFN-γ is a pleiotropic immunomodulator and possesses intrinsic antiviral activity. We studied its significance in the development of antiviral immune responses by using IFN-γ receptor-deficient (IFN-γR(- /-)) mice. After inoculation with live attenuated pseudorabies virus (PRV), the mutant mice showed no infectivity titers in various tissues, and transient viral Ag expression only in the spleen, similar as in wild-type mice. However, the absence of the IFN-γR resulted in increased proliferative splenocyte responses. The PRV-immune animals showed a normal IFN-γ and IL-2 production, without detectable IL-4, and with decreased IL-10 secretion in response to viral Ag or Con A. Immunohistochemically, an increased ratio of IFN-γ:IL-4-producing spleen cells was found. After immunization with either live attenuated or inactivated PRV, IFN-γR(-/-) mice produced significantly less antiviral Ab, and more succumbed to challenge infection than the intact control animals. The reduction in Ab titers in the mutant mice correlated with lower protection by their sera in transfer experiments. Our data demonstrate that ablation of the IFN-γ receptor surprisingly does not inhibit the generation of antiviral Th1-type and increase Th2-type cytokine responses. However, it profoundly impairs the generation of protective antiviral Ab.</p