Evaluation of the immune response to RTS,S/AS01 and RTS,S/AS02 adjuvanted vaccines : randomized, double-blind study in malaria-naïve adults

This phase II, randomized, double-blind study evaluated the immunogenicity of RTS, S vaccines containing Adjuvant System AS 01 or AS 02 as compared with non-adjuvanted RTS, S in healthy, malaria-naive adults (NCT00443131). Thirty-six subjects were randomized (1:1:1) to receive RTS, S/AS 01, RTS, S/AS 02, or RTS, S/saline at months 0, 1, and 2. Antibody responses to Plasmodium falciparum circumsporozoite (CS) and hepatitis B surface (HBs) antigens were assessed and cell-mediated immune responses evaluated by flow cytometry using intracellular cytokine staining on peripheral blood mononuclear cells. Anti-CS antibody avidity was also characterized. Safety and reactogenicity after each vaccine dose were monitored. One month after the third vaccine dose, RTS, S/AS 01 (160.3 EU/mL [95%CI: 114.1-225.4]) and RTS, S/AS 02 (77.4 EU/mL (95%CI: 47.3-126.7)) recipients had significantly higher anti-CS antibody geometric mean titers (GMTs) than recipients of RTS, S/saline (12.2 EU/mL (95%CI: 4.8-30.7); P < 0.0001 and P = 0.0011, respectively). The anti-CS antibody GMT was significantly higher with RTS, S/AS 01 than with RTS, S/AS 02 (P = 0.0135). Anti-CS antibody avidity was in the same range in all groups. CS- and HBs-specific CD4(+) T cell responses were greater for both RTS, S/AS groups than for the RTS, S/saline group. Reactogenicity was in general higher for RTS, S/AS compared with RTS, S/saline. Most grade 3 solicited adverse events (AEs) were of short duration and grade 3 solicited general AEs were infrequent in the 3 groups. No serious adverse events were reported. In conclusion, in comparison with non-adjuvanted RTS, S, both RTS, S/AS vaccines exhibited better CS-specific immune responses. The anti-CS antibody response was significantly higher with RTS, S/AS 01 than with RTS, S/AS 02. The adjuvanted vaccines had acceptable safety profiles

Contrôle de la chiralité axiale à l’aide d’arynes et en absence de métaux de transition

International audienceThe modular construction of enantioenriched biaryl derivatives is presented. This approach is based on (a) an almost quantitative access to polybrominated precursors via a transition metal-free aryl-aryl coupling, the ARYNE-coupling, (b) the regioselective introduction of a traceless chiral auxiliary (an enantiopure para-tolylsulfinyl group), (c) the chemoselective functionalization of this auxiliary and (d) subsequent regioselective functionalization of the remaining bromine atoms without any racemization during these steps. Next, the atropo-selective coupling of in situ generated arynes and aryllithiums bearing various chiral auxiliaries (tert-butylsulfoxide, para-tolylsulfoxide, tartrate-derived chiral diethers and oxazolines) is described and applied to the formal synthesis of (-)-steganacin. La construction modulaire de dérivés biaryliques énantioenrichis est présentée. Cette approche est basée sur (a) un accès quasi quantitatif aux précurseurs polybromés via un 2 couplage aryle-aryle sans métaux de transition, le couplage ARYNE, (b) l'introduction régiosélective d'un auxiliaire chiral (un groupe para-tolylsulfinyl énantiopur), (c) la fonctionnalisation chimiosélective de cet auxiliaire et (d) la fonctionnalisation régiosélective subséquente des atomes de brome restants sans racémisation au cours de ces étapes. Ensuite, le couplage atropo-sélectif à l'aide d'arynes générés in situ et d'aryllithiums portant divers auxiliaires chiraux (tert-butylsulfoxyde, para-tolylsulfoxide, diéthers dérivés du tartrate et des oxazolines chirales) est décrit et appliqué à la synthèse formelle de la (-)-stéganacine

A monoclonal antibody-based immunoassay to measure the antibody response against the repeat region of the circumsporozoite protein of Plasmodium falciparum

Background: The malaria vaccine candidate RTS, S/AS01 (GSK Vaccines) induces high IgG concentration against the circumsporozoite protein (CSP) of Plasmodium falciparum. In human vaccine recipients circulating anti-CSP antibody concentrations are associated with protection against infection but appear not to be the correlate of protection. However, in a humanized mouse model of malaria infection prophylactic administration of a human monoclonal antibody (MAL1C), derived from a RTS, S/AS01-immunized volunteer, directed against the CSP repeat region, conveyed full protection in a dose-dependent manner suggesting that antibodies alone are able to prevent P. falciparum infection when present in sufficiently high concentrations. A competition ELISA was developed to measure the presence of MAL1C-like antibodies in polyclonal sera from RTS, S/AS01 vaccine recipients and study their possible contribution to protection against infection. Results: MAL1C-like antibodies present in polyclonal vaccine-induced sera were evaluated for their ability to compete with biotinylated monoclonal antibody MAL1C for binding sites on the capture antigen consisting of the recombinant protein encompassing 32 NANP repeats of CSP (R32LR). Serum samples were taken at different time points from participants in two RTS, S/AS01 vaccine studies (NCT01366534 and NCT01857869). Vaccine-induced protection status of the study participants was determined based on the outcome of experimental challenge with infected mosquito bites after vaccination. Optimal conditions were established to reliably detect MAL1C-like antibodies in polyclonal sera. Polyclonal anti-CSP antibodies and MAL1C-like antibody content were measured in 276 serum samples from RTS, S/AS01 vaccine recipients using the standard ELISA and MAL-1C competition ELISA, respectively. A strong correlation was observed between the results from these assays. However, no correlation was found between the results of either assay and protection against infection. Conclusions: The competition ELISA to measure MAL1C-like antibodies in polyclonal sera from RTS, S/AS01 vaccine recipients was robust and reliable but did not reveal the elusive correlate of protection

Mandible Behavior in Obstructive Sleep Apnea Patients Under CPAP Treatment

Aim: To investigate whether obstructive sleep apnea (OSA) patients present different behaviors of mandible movements before and under CPAP therapy. Materials and Methodology: In this retrospective study, patients were selected according to inclusion criteria: both the diagnostic polysomnography recording showing an OSA with an apnea-hypopnea index (AHI) greater than 25 (n/h) and the related CPAP therapy control recordings were available, presence of mandible movement and mask pressure signals in the recordings, and tolerance to the applied positive pressure. Statistical analysis on four parameters, namely the apneahypopnea index (AHI), the arousal index (ArI), the average of the mandible lowering during sleep (aLOW), and the average amplitude of the oscillations of the mandible movement signal (aAMPL), was performed on two sets of recordings: OSA and CPAP therapy. Results: Thirty-four patients satisfied the inclusion criteria, thus both OSA and CPAP groups included thirty-four recordings each. Significant difference (p < 0.001) was found in the OSA group compared with the CPAP group when considering either the four parameters or only the two ones related to mandible movements. Conclusions: When an efficient CPAP pressure is applied, the mouth is less open and presents fewer broad sharp closure movements, and oscillating mandible movements are absent or very small.Peer reviewe

Impact of Complex-Logic Cell Layout on the Single-Event Transient Sensitivity

International audienceThe design methodology based on standard cells is widely used in a broad range of VLSI applications. Further, several optimization algorithms can be employed to address different constraints such as power consumption or reliability. This work evaluates the implications of the usage of complex-logic cells from a 45 nm Standard-Cell library to the Single-Event Transient sensitivity under heavy ions. Results show that even though a reduction in the layout area is obtained when adopting complex-logic gates, a slight reduction in the total sensitive area of the circuit is observed. Moreover, the effectiveness of logical masking can be suppressed, leading to a higher SET cross-section

A dose-ranging study in older adults to compare the safety and immunogenicity profiles of MF59®-adjuvanted and non-adjuvanted seasonal influenza vaccines following intradermal and intramuscular administration

Strategies to optimize responses to seasonal influenza vaccination in older adults include the use of adjuvants, higher antigen doses, and intradermal delivery. In this study adults aged >= 65 years (n = 450) received a single dose of 1 of 2 non-adjuvanted trivalent influenza vaccine (TIV) formulations administered intradermally (ID), both containing 6 mu g of A/H1N1 and B, differing in A/H3N2 content (6 mu g or 12 mu g), or a single dose of 1 of 8 TIV formulations administered intramuscularly (IM) all containing 15 mu g of A/H1N1 and B, differing in A/H3N2 hemagglutinin (HA) content (15 mu g or 30 mu g) and/or in MF59 (R) adjuvant content (0%, 25%, 50%, or 100% of the standard dose). This paper focuses on the comparisons of low-dose non-adjuvanted ID, full-dose non-adjuvanted IM and full-dose MF59-adjuvanted IM formulations (n = 270). At day 22 post-vaccination, at least one European licensure immunogenicity criterion was met by all groups against all 3 strains; however, all three criteria were met against all 3 vaccine strains by the low-dose non-adjuvanted ID and the full-dose MF59-adjuvanted IM groups only. The full-dose MF59-adjuvanted IM group elicited significantly higher immune response vs. the low-dose non-adjuvanted ID formulations for most comparisons. The full-dose MF59 adjuvanted IM groups were associated with increased pain at the site of injection (P < 0.01) compared to the ID groups, and the low-dose non-adjuvanted ID groups were associated with increased erythema, induration, and swelling at the injection site (P < 0.0001) and unsolicited AEs compared with the IM groups. There were no differences between IM and ID groups in the frequencies of subjects experiencing solicited systemic reactions. Overall, while MF59 adjuvantation increased pain at the site of injection, and intradermal delivery increased unsolicited adverse events, erythema, induration, and swelling at the injection site, both strategies of vaccination strongly enhanced the immunogenicity of seasonal influenza vaccine in older adults compared with conventional non-adjuvanted intramuscular delivery

Validation of an enzyme-linked immunosorbent assay for the quantification of human IgG directed against the repeat region of the circumsporozoite protein of the parasite Plasmodium falciparum.

BACKGROUND: Several pre-erythrocytic malaria vaccines based on the circumsporozoite protein (CSP) antigen of Plasmodium falciparum are in clinical development. Vaccine immunogenicity is commonly evaluated by the determination of anti-CSP antibody levels using IgG-based assays, but no standard assay is available to allow comparison of the different vaccines. METHODS: The validation of an anti-CSP repeat region enzyme-linked immunosorbent assay (ELISA) is described. This assay is based on the binding of serum antibodies to R32LR, a recombinant protein composed of the repeat region of P. falciparum CSP. In addition to the original recombinant R32LR, an easy to purify recombinant His-tagged R32LR protein has been constructed to be used as solid phase antigen in the assay. Also, hybridoma cell lines have been generated producing human anti-R32LR monoclonal antibodies to be used as a potential inexhaustible source of anti-CSP repeats standard, instead of a reference serum. RESULTS: The anti-CSP repeats ELISA was shown to be robust, specific and linear within the analytical range, and adequately fulfilled all validation criteria as defined in the ICH guidelines. Furthermore, the coefficient of variation for repeatability and intermediate precision did not exceed 23%. Non-interference was demonstrated for R32LR-binding sera, and the assay was shown to be stable over time. CONCLUSIONS: This ELISA, specific for antibodies directed against the CSP repeat region, can be used as a standard assay for the determination of humoral immunogenicity in the development of any CSP-based P. falciparum malaria vaccine

Transition-Metal-Free Synthesis of a Known Intermediate in the Formal Synthesis of (-)-Steganacin

International audienceThe formal synthesis of both enantiomers of a natural axially chiral biaryl, steganacin is reported. The previously developed atropo-diastereoselective coupling of an aryne and an aryllithium (the 'ARYNE coupling') allows for this synthesis. In each step, the axial configuration of the biaryl could be maintained. The key intermediate of literature was accessed without using transition metals, demonstrating the interest of the ARYNE coupling as a complement or an alternative to transition metal-catalyzed couplings

Non-Abelian adiabatic geometric transformations in a cold Strontium gas

Topology, geometry, and gauge fields play key roles in quantum physics as exemplified by fundamental phenomena such as the Aharonov-Bohm effect, the integer quantum Hall effect, the spin Hall, and topological insulators. The concept of topological protection has also become a salient ingredient in many schemes for quantum information processing and fault-tolerant quantum computation. The physical properties of such systems crucially depend on the symmetry group of the underlying holonomy. We study here a laser-cooled gas of strontium atoms coupled to laser fields through a 4-level resonant tripod scheme. By cycling the relative phases of the tripod beams, we realize non-Abelian SU(2) geometrical transformations acting on the dark-states of the system and demonstrate their non-Abelian character. We also reveal how the gauge field imprinted on the atoms impact their internal state dynamics. It leads to a new thermometry method based on the interferometric displacement of atoms in the tripod beams

Evaluation of cellular immunity to mumps in vaccinated individuals with or without circulating antibodies up to 16 years after their last vaccination

In this observational study, mumps-specific in vitro lympho-proliferation was measured in 24 subjects with low antibody titers and 24 subjects with high antibody titers who received their last vaccine dose up to 16 years previously. Overall, a significant lymphoproliferative response was found in 32 subjects (66.7%)-namely, in 13 (54.2%) of those with low antibody titers and 19 (79.2%) of those with high antibody titers. The mean stimulation index for subjects with low antibody titers was 4.47, whereas that for subjects with high antibody titers was 8.31 (P = .032). Mumps vaccine-induced cell-mediated immunity appears to be more persistent than the antibody response