A vaccine remains a priority in the global fight against malaria. Here, we report on a single-center, randomized, double-blind, placebo and adjuvant-controlled, dose escalation phase 1a safety and ...immunogenicity clinical trial of full-length Plasmodium falciparum merozoite surface protein 1 (MSP1) in combination with GLA-SE adjuvant. Thirty-two healthy volunteers were vaccinated at least three times with MSP1 plus adjuvant, adjuvant alone, or placebo (24:4:4) to evaluate the safety and immunogenicity. MSP1 was safe, well tolerated and immunogenic, with all vaccinees sero-converting independent of the dose. The MSP1-specific IgG and IgM titers persisted above levels found in malaria semi-immune humans for at least 6 months after the last immunization. The antibodies were variant- and strain-transcending and stimulated respiratory activity in granulocytes. Furthermore, full-length MSP1 induced memory T-cells. Our findings encourage challenge studies as the next step to evaluate the efficacy of full-length MSP1 as a vaccine candidate against falciparum malaria (EudraCT 2016-002463-33).
The purinoreceptor P2X7 is expressed on subsets of T cells and mediates responses of these cells to extracellular nucleotides such as ATP or NAD(+). We identified P2X7 as a molecule highly ...up-regulated on conventional CD8alphabeta(+) and unconventional CD8alphaalpha(+) T cells of the intestinal epithelium of mice. In contrast, CD8(+) T cells derived from spleen, mesenteric lymph nodes, and liver expressed only marginal levels of P2X7. However, P2X7 was highly up-regulated on CD8(+) T cells from spleen and lymph nodes when T cells were activated in the presence of retinoic acid. High P2X7 expression on intestinal CD8(+) T cells as well as on CD8(+) T cells incubated with retinoic acid resulted in enhanced sensitivity of cells to extracellular nucleotides. Both cell populations showed a high level of apoptosis following incubation with NAD(+) and the ATP derivative 2',3'-O-(benzoyl-4-benzoyl)-ATP, and injection of NAD(+) caused selective in vivo depletion of intestinal CD8(+) T cells. Following oral infection with Listeria monocytogenes, P2X7-deficient mice showed similar CD8(+) T cell responses in the spleen, but enhanced responses in the intestinal mucosa, when compared with similarly treated wild-type control mice. Overall, our observations define P2X7 as a new regulatory element in the control of CD8(+) T cell responses in the intestinal mucosa.
High-density peptide arrays are an excellent means to profile anti-plasmodial antibody responses. Different protein intrinsic epitopes can be distinguished, and additional insights are gained, when ...compared with assays involving the full-length protein. Distinct reactivities to specific epitopes within one protein may explain differences in published results, regarding immunity or susceptibility to malaria. We pursued three approaches to find specific epitopes within important plasmodial proteins, (1) twelve leading vaccine candidates were mapped as overlapping 15-mer peptides, (2) a bioinformatical approach served to predict immunogenic malaria epitopes which were subsequently validated in the assay, and (3) randomly selected peptides from the malaria proteome were screened as a control. Several peptide array replicas were prepared, employing particle-based laser printing, and were used to screen 27 serum samples from a malaria-endemic area in Burkina Faso, West Africa. The immunological status of the individuals was classified as "protected" or "unprotected" based on clinical symptoms, parasite density, and age. The vaccine candidate screening approach resulted in significant hits in all twelve proteins and allowed us (1) to verify many known immunogenic structures, (2) to map B-cell epitopes across the entire sequence of each antigen and (3) to uncover novel immunogenic epitopes. Predicting immunogenic regions in the proteome of the human malaria parasite Plasmodium falciparum, via the bioinformatics approach and subsequent array screening, confirmed known immunogenic sequences, such as in the leading malaria vaccine candidate CSP and discovered immunogenic epitopes derived from hypothetical or unknown proteins.
Sterile protection against malaria infection can be achieved by the inoculation of intact sporozoites while treating concomitantly with the 4-aminoquinoline chloroquine. We present an analysis of ...protective immunity elicited by successive immunization with Plasmodium berghei sporozoites under chemoprophylaxis. Immunization resulted in a protective, stage-specific immune response. Protection appeared to be mediated by CD8+ T cells and was abrogated upon their specific depletion. Adoptive transfer of splenocytes rendered recipient animals resistant to sporozoite infection, but not to blood-stage challenge. Immunization with sporozoites under chemoprophylaxis results in robust immunity, and the presence of blood-stage infection at sporozoite immunization had no downregulating effect on the protective immune response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The WHO declared the COVID-19 outbreak a public health emergency of international concern. The causative agent of this acute respiratory disease is a newly emerged coronavirus, named SARS-CoV-2, ...which originated in China in late 2019. Exposure to SARS−CoV−2 leads to multifaceted disease outcomes from asymptomatic infection to severe pneumonia, acute respiratory distress and potentially death. Understanding the host immune response is crucial for the development of interventional strategies. Humoral responses play an important role in defending viral infections and are therefore of particular interest. With the aim to resolve SARS-CoV-2-specific humoral immune responses at the epitope level, we screened clinically well-characterized sera from COVID-19 patients with mild and severe disease outcome using high-density peptide microarrays covering the entire proteome of SARS-CoV-2. Moreover, we determined the longevity of epitope-specific antibody responses in a longitudinal approach. Here we present IgG and IgA-specific epitope signatures from COVID-19 patients, which may serve as discriminating prognostic or predictive markers for disease outcome and/or could be relevant for intervention strategies.
Operieren und Lehren [Operating and Teaching] Brauer, Robert B.; Heiss, Kirsten I.; Mornau, Max ...
GMS Zeitschrift für Medizinische Ausbildung,
05/2006, Letnik:
23, Številka:
2
Journal Article
Recenzirano
Odprti dostop
english According to the legal regulations of medical education (10/01/2003) in Germany students have to pass at least one week of surgical training in a block practical. We show the ...12-months-experience with this new educational model in our surgery department. All practical lessons have been organized in a three-weeks-block practical for 75 students. Alternating with other specialties the block practical takes part four times a year for a total of 300 students. In the first week, the so-called skills-training week, medical students are trained in techniques of skin-suturing and hand-sewn enteral anastomoses, osteosynthesis, wound dressings and plaster bandage in newly designed seminars. These practical techniques are applied in the second and third week, the so-called tutor-coaching weeks. Students randomly rotate through all available wards, clinics and operating rooms on a day-by-day basis. After completion of the block practical students have the opportunity to evaluate every single teaching session through online marks. Apart from the organization 95% of the students rated the first week with practical seminars with highest marks. The daily rotation through the different clinics has been well accepted by the students. It has to be emphasized that the students felt much more welcome and taken seriously in the new educational model of the block practical than in former surgery courses. german Kurzdarstellung: Die Umsetzung der neuen Approbationsordnung (1.10.2003) für Ärzte erforderte eine erhebliche Umstellung der Studierendenausbildung. An einer chirurgischen Universitätsklinik wurde der gesamte praktische Unterricht in ein dreiwöchiges Blockpraktikum, bestehend aus Skilltraining und Tutorcoaching integriert. Vorgestellt werden die Erfahrungen mit den veränderten Lehrformen in den letzten 12 Monaten. Zusammenfassung: In der neuen Approbationsordnung (1.10.2003) wurde für das Fach Chirurgie die Durchführung eines mindestens einwöchigen Blockpraktikums in der klinischen Ausbildung festgelegt. Am Beispiel einer Chirurgischen Universitätsklinik wird die Erfahrung der ersten 12 Monate mit den neuen Lehrformen vorgestellt. Alle praktischen Lehrveranstaltungen der chirurgischen Klinik wurden innerhalb eines dreiwöchigen Blockpraktikums für jeweils 75 Studierende integriert. Alternierend mit den anderen Fächern findet das Blockpraktikum insgesamt viermal im Jahr für 300 Studierende statt. In der ersten Woche dem sogenannten Skilltraining werden praktische Fähigkeiten in völlig neu konzipierten Seminaren über Naht- und Knotentechnik, Osteosynthesetechniken, Verbands- und Gipstechnik und Anastomosen mit selbstständig durchgeführten praktischen Übungen durchgeführt. In der zweiten und dritten Woche werden im Rahmen des Tutorcoachings die erlernten Fähigkeiten im klinischen Alltag angewendet. Die Studierenden rotieren täglich durch alle verfügbaren Stationen, Ambulanzen und Operationssäle. Nach Abschluss des Blockpratikums erfolgte die online Evaluation einzelner Lehrveranstaltungen durch die Studierenden. Neben der Organisation wurde vor allem die erste Woche des rein praktisch orientierten Skilltrainings mit bis zu 95% der Studierenden mit sehr gut und gut bewertet. Auch die Verteilung über die verschiedenen chirurgischen Kliniken fand sehr große Zustimmung bei den Studierenden. Hervorgehoben wird, dass sich die Studierenden im Gegensatz zu den bisher stattfindenden Lehrveranstaltungen der alten Approbationsordnung innerhalb des Blockpraktikums willkommen und ernst genommen gefühlt haben.
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