Chimeric hemagglutinin split vaccines elicit broadly cross-reactive antibodies and protection against group 2 influenza viruses in mice.

Seasonal influenza virus vaccines are effective when they are well matched to circulating strains. Because of antigenic drift/change in the immunodominant hemagglutinin (HA) head domain, annual vaccine reformulations are necessary to maintain a match with circulating strains. In addition, seasonal vaccines provide little to no protection against newly emerging pandemic strains. Sequential vaccination with chimeric HA (cHA) constructs has been proven to direct the immune response toward the immunosubdominant but more conserved HA stalk domain. In this study, we show that immunization with group 2 cHA split vaccines in combination with the CpG 1018 adjuvant elicits broadly cross-reactive antibodies against all group 2 HAs, as well as systemic and local antigen-specific T cell responses. Antibodies elicited after sequential vaccination are directed to conserved regions of the HA such as the stalk and the trimer interface and also to the N2 neuraminidase (NA). Immunized mice were fully protected from challenge with a broad panel of influenza A viruses.

[Extended preoperative speech audiometric diagnostics for cochlear implant treatment]. / Erweiterte präoperative sprachaudiometrische Diagnostik im Rahmen der Cochleaimplantatversorgung.

BACKGROUND: For severe hearing loss and even profound deafness, cochlear implants (CIs) have become the treatment of choice. For establishment of the CI indication, the preoperative Freiburger monosyllabic word recognition (EV) at 65 dB SPL in free field with a hearing aid (EVHG65) and the maximal understanding (mEV) without a hearing aid with headphones results are important. The goal of this retrospective study was to analyse the correlation of word recognition with a hearing aid at 80 dB SPL (EVHG80) and mEV. This represents an extension to measuring EVHG65 compared to mEV and to pure-tone audiometry (4FPTA). METHODS: In this study, word recognition with and without a hearing aid was retrospectively analysed for 661 ears. Inclusion criterium was CI implantation at a later date. RESULTS: During preoperative CI diagnostics, an mEV of 0% was found in 334 ears. The EVHG65 for 485 ears and the EVHG80 for 335 ears were also 0%. The EV with hearing aid was found to worsen with increasing 4FPTA at both sound pressure levels, although this effect was smaller at 80 dB SPL than at 65 dB SPL. Including only ears with mEV > 0 % (N = 260 ears), a stronger correlation between EVHG80 and mEV with a difference of (-4.0 ± 16.4%) in comparison to EVHG65 and mEV with a difference of (-18.3 ± 16.7%) is seen. This shows a significant difference between mEV and EVHG80 compared to mEV and EVHG65. CONCLUSION: At a sound pressure level of 65 dB SPL, EV with hearing aid often does not show the accordance with mEV specified by hearing aid and CI guidelines. The EVHG80 correlates better with mEV than EVHG65. For clinical diagnosis it is rational to measure speech discrimination with hearing aid at levels higher than 65 dB SPL.

Facilitation properties in electrically evoked compound action potentials depending on spatial location and on threshold.

Spiral ganglion neurons (SGNs) facilitation properties can be recorded utilizing electrically evoked compound action potential (ECAP). While intracochlear variation of the ECAP threshold in relation to its electrode channel is reported, no study investigated its impact on facilitation. In this study, we quantified intracochlear variation of the facilitation properties in cochlear implants (CI) using ECAPs. We hypothesized that the facilitation effect is dependent on the electrode channel and its ECAP threshold. Therefore, ECAPs were recorded in 23 CI subjects. For each subject, five default (channel-derived) and up to two additional (threshold-derived) stimulation sites were defined. Facilitation was quantified by the paradigm introduced by (Hey et al., 2017) with optimized parameter settings. For each channel the maximum facilitated amplitude was determined by a series of ECAP measurements. A linear mixed-effects model was used to investigate the impact of the electrode channel and ECAP threshold on the maximum facilitated amplitude. The maximum facilitated amplitude was found to be dependent on the ECAP threshold and independent on the electrode channel. We conclude that the facilitation paradigm is a useful and feasible tool to gain local information on the SGNs temporal processing patterns.

Bioprocess development for universal influenza vaccines based on inactivated split chimeric and mosaic hemagglutinin viruses.

Seasonal influenza viruses account for 1 billion infections worldwide every year, including 3-5 million cases of severe illness and up to 650,000 deaths. The effectiveness of current influenza virus vaccines is variable and relies on the immunodominant hemagglutinin (HA) and to a lesser extent on the neuraminidase (NA), the viral surface glycoproteins. Efficient vaccines that refocus the immune response to conserved epitopes on the HA are needed to tackle infections by influenza virus variants. Sequential vaccination with chimeric HA (cHA) and mosaic HA (mHA) constructs has proven to induce immune responses to the HA stalk domain and conserved epitopes on the HA head. In this study, we developed a bioprocess to manufacture cHA and mHA inactivated split vaccines and a method to quantify HA with a prefusion stalk based on a sandwich enzyme-linked immunosorbent assay. Virus inactivation with beta-propiolactone (ßPL) and splitting with Triton X-100 yielded the highest amount of prefusion HA and enzymatically active NA. In addition, the quantity of residual Triton X-100 and ovalbumin (OVA) was reduced to very low levels in the final vaccine preparations. The bioprocess shown here provides the basis to manufacture inactivated split cHA and mHA vaccines for pre-clinical research and future clinical trials in humans, and can also be applied to produce vaccines based on other influenza viruses.

Extended Preoperative Audiometry for Outcome Prediction and Risk Analysis in Patients Receiving Cochlear Implants.

BACKGROUND: The outcome of cochlear implantation has improved over the last decades, but there are still patients with less benefit. Despite numerous studies examining the cochlear implant (CI) outcome, variations in speech comprehension with CI remains incompletely explained. The aim of this study was therefore to examine preoperative pure-tone audiogram and speech comprehension as well as aetiology, to investigate their relationship with postoperative speech comprehension in CI recipients. METHODS: A retrospective study with 664 ears of 530 adult patients was conducted. Correlations between the target variable postoperative word comprehension with the preoperative speech and sound comprehension as well as aetiology were investigated. Significant correlations were inserted into multivariate models. Speech comprehension measured as word recognition score at 70 dB with CI was analyzed as (i) a continuous and (ii) a dichotomous variable. RESULTS: All variables that tested preoperative hearing were significantly correlated with the dichotomous target; with the continuous target, all except word comprehension at 65 dB with hearing aid. The strongest correlation with postoperative speech comprehension was seen for monosyllabic words with hearing aid at 80 dB. The preoperative maximum word comprehension was reached or surpassed by 97.3% of CI patients. Meningitis and congenital diseases were strongly negatively associated with postoperative word comprehension. The multivariate model was able to explain 40% of postoperative variability. CONCLUSION: Speech comprehension with hearing aid at 80 dB can be used as a supplementary preoperative indicator of CI-aided speech comprehension and should be measured regularly in the clinical routine. Combining audiological and aetiological variables provides more insights into the variability of the CI outcome, allowing for better patient counselling.

Optimizing the efficiency of ECAP measurements due to interpolation.

BACKGROUND: Thresholds of electrically evoked compound action potentials (TECAP) may serve as starting points for electrophysiologically based fitting of cochlear implants. Absent TECAP data at single electrodes reduces the number of data points available for fitting and can be substituted by interpolation of measured data points. AIM: To compare complete TECAP profiles with interpolated TECAP profiles of 5/22 (∼22.7%) and 11/22 (50%) electrode contacts. MATERIAL AND METHODS: Single-centre, retrospective, observational study of data from 624 ears implanted with a Slim Modiolar (CI ×32) or Contour Advance (CI ×12, CI24RE(CA)) electrode array (Cochlear Ltd). The deviation of the complete measured TECAP profile from the same profile with missing and therefore interpolated TECAP values was quantified. RESULTS: Interpolated TECAP profiles significantly differ from complete measured profiles especially at the basal and apical electrodes. Reference data for Slim Modiolar and Contour Advance electrodes mean profiles are provided. CONCLUSIONS AND SIGNIFICANCE: Reducing the number of measured TECAP electrodes has to be weighted against losses in the TECAP accuracy of interpolated values. A clinically acceptable compromise may be a reduction from 22 to 11 even non-equidistant data points. While reducing ECAP measurement time, it is accompanied by a minimal loss of accuracy of the TECAP threshold profile.