Safety and Immunogenicity of a ChAd155-Vectored Respiratory Syncytial Virus (RSV) Vaccine in Healthy RSV-Seropositive Children 12-23 Months of Age.

BACKGROUND: Safe and effective respiratory syncytial virus (RSV) vaccines remain elusive. This was a phase I/II trial (NCT02927873) of ChAd155-RSV, an investigational chimpanzee adenovirus-RSV vaccine expressing 3 proteins (fusion, nucleoprotein, and M2-1), administered to 12-23-month-old RSV-seropositive children followed up for 2 years after vaccination. METHODS: Children were randomized to receive 2 doses of ChAd155-RSV or placebo (at a 1:1 ratio) (days 1 and 31). Doses escalated from 0.5 × 1010 (low dose [LD]) to 1.5 × 1010 (medium dose [MD]) to 5 × 1010 (high dose [HD]) viral particles after safety assessment. Study end points included anti-RSV-A neutralizing antibody (Nab) titers through year 1 and safety through year 2. RESULTS: Eighty-two participants were vaccinated, including 11, 14, and 18 in the RSV-LD, RSV-MD, and RSV-HD groups, respectively, and 39 in the placebo groups. Solicited adverse events were similar across groups, except for fever (more frequent with RSV-HD). Most fevers were mild (≤38.5°C). No vaccine-related serious adverse events or RSV-related hospitalizations were reported. There was a dose-dependent increase in RSV-A Nab titers in all groups after dose 1, without further increase after dose 2. RSV-A Nab titers remained higher than prevaccination levels at year 1. CONCLUSIONS: Three ChAd155-RSV dosages were found to be well tolerated. A dose-dependent immune response was observed after dose 1, with no observed booster effect after dose 2. Further investigation of ChAd155-RSV in RSV-seronegative children is warranted. CLINICAL TRIALS REGISTRATION: NCT02927873.

Respiratory syncytial virus (RSV) is among the main causes of bronchiolitis and pneumonia regularly leading to hospitalization in children. A safe and effective vaccine to prevent RSV infection in this age group has not yet been found, despite great efforts over several decades. This study tested a new candidate RSV vaccine, expressing 3 important pieces of the virus, in toddlers who already had a previous RSV infection. The vaccine was generally well tolerated. Vaccination triggered antibodies against RSV that were able to block the virus in laboratory tests and that persisted for 1 year.

Technical note: Characteristics of the energy spread kernels of scattered radiation in an x-ray room.

PURPOSE: To describe the scattered radiation spectra inside an x-ray room for different scattering conditions. METHODS: Monte Carlo simulations of an x-ray room using phantoms of different size, varying field sizes, and a range of mono-energetic beams were carried out. For each energy, the particle fluence spectrum of scattered photons was collected at different spherical zones to describe the radiation reaching the different boundaries of the x-ray room. The effect on the scattered spectrum of the room floor was also considered. RESULTS: The scattered spectra for mono-energetic primary beams at a given spherical zone give rise to oriented energy spread kernels (OESKs) that can be used to calculate the scattered spectrum for any poly-energetic beam at that zone. Despite the large differences, which can be seen in the OESKs when the scattering conditions vary, an important invariance is also observed: the position of the broad scatter peak for a given primary energy and zone. CONCLUSIONS: The result of breaking down the calculation of the scattered radiation spectrum into the different factors that influence it allows estimating the spectrum in a wide range of situations. The invariant position of the broad scatter peak can be used to estimate the highest energy of the scattered photons for a given primary energy and zone, which may determine radiation shielding needs.

First-in-Human Randomized Study to Assess the Safety and Immunogenicity of an Investigational Respiratory Syncytial Virus (RSV) Vaccine Based on Chimpanzee-Adenovirus-155 Viral Vector-Expressing RSV Fusion, Nucleocapsid, and Antitermination Viral Proteins in Healthy Adults.

BACKGROUND: Respiratory syncytial virus (RSV) disease is a major cause of infant morbidity and mortality. This Phase I, randomized, observer-blind, placebo- and active-controlled study evaluated an investigational vaccine against RSV (ChAd155-RSV) using the viral vector chimpanzee-adenovirus-155, encoding RSV fusion (F), nucleocapsid, and transcription antitermination proteins. METHODS: Healthy 18-45-year-old adults received ChAd155-RSV, a placebo, or an active control (Bexsero) at Days (D) 0 and 30. An escalation from a low dose (5 × 109 viral particles) to a high dose (5 × 1010 viral particles) occurred after the first 16 participants. Endpoints were solicited/unsolicited and serious adverse events (SAEs), biochemical/hematological parameters, cell-mediated immunogenicity by enzyme-linked immunospot, functional neutralizing antibodies, anti RSV-F immunoglobin (Ig) G, and ChAd155 neutralizing antibodies. RESULTS: There were 7 participants who received the ChAd155-RSV low dose, 31 who received the ChAd155-RSV high dose, 19 who received the placebo, and 15 who received the active control. No dose-related toxicity or attributable SAEs at the 1-year follow-up were observed. The RSV-A neutralizing antibodies geometric mean titer ratios (post/pre-immunization) following a high dose were 2.6 (D30) and 2.3 (D60). The ratio of the fold-rise (D0 to D30) in anti-F IgG over the fold-rise in RSV-A-neutralizing antibodies was 1.01. At D7 after the high dose of the study vaccine, the median frequencies of circulating B-cells secreting anti-F antibodies were 133.3/106 (IgG) and 16.7/106 (IgA) in peripheral blood mononuclear cells (PBMCs). The median frequency of RSV-F-specific interferon γ-secreting T-cells after a ChAd155-RSV high dose was 108.3/106 PBMCs at D30, with no increase after the second dose. CONCLUSIONS: In adults previously naturally exposed to RSV, ChAd155-RSV generated increases in specific humoral and cellular immune responses without raising significant safety concerns. CLINICAL TRIALS REGISTRATION: NCT02491463.

Adjuvant effect of TLR7 agonist adsorbed on aluminum hydroxide (AS37): A phase I randomized, dose escalation study of an AS37-adjuvanted meningococcal C conjugated vaccine.

An adjuvant system (AS37) has been developed containing a synthetic toll-like receptor agonist (TLR7a). We conducted a phase I randomized, observer-blind, dose-escalation study to assess the safety and immunogenicity of an investigational AS37-adjuvanted meningococcus C (MenC) conjugate vaccine in healthy adults (NCT02639351). A control group received a licensed MenC conjugate alum-adjuvanted vaccine. Eighty participants were randomized to receive one dose of control or investigational vaccine containing AS37 (TLR7a dose 12.5, 25, 50, 100 µg). All vaccines were well tolerated, apart from in the TLR7a 100 µg dose group, which had three reports (18.8%) of severe systemic adverse events. Four weeks after vaccination, human complement serum bactericidal assay seroresponse rates against MenC were 56-81% in all groups, and ELISA seroresponses were ≥81% for all AS37-adjuvanted vaccine groups (100% in 50 and 100 µg dose groups) and 88% in the control group. Antibody responses were maintained at six months after vaccination.

Safety and immunogenicity of a respiratory syncytial virus fusion glycoprotein F subunit vaccine in healthy adults: Results of a phase 1, randomized, observer-blind, controlled, dosage-escalation study.

INTRODUCTION: Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections in infants. An investigational vaccine using an engineered recombinant RSV fusion glycoprotein in its post-fusion conformation (RSV F subunit vaccine) has been developed to protect young infants via maternal immunization. This first-in-human, phase I, observer-blind study (NCT02298179) evaluated the safety and immunogenicity of different dosages and formulations of RSV F subunit vaccine in healthy non-pregnant women and men aged 18-45 years. METHODS: Participants were enrolled (1:1:1) in a stepwise dosage-escalation manner into three cohorts to receive RSV F subunit vaccine containing 45 µg, 90 µg and 135 µg of RSV F glycoprotein. Within each cohort, participants were randomized (1:1:1:1) to receive two doses of RSV F subunit vaccine with (aluminum hydroxide or MF59) or without adjuvant, or placebo, ≥28 days apart. Safety (until day 365 post-dose 2), anti-RSV neutralizing antibodies (NAbs) and serum total binding antibodies to RSV F protein (until day 181 post-dose 1) were evaluated. RESULTS: All formulations were well-tolerated. No vaccine-related serious adverse events were reported. All participants were seropositive for anti-RSV NAbs at baseline, with geometric mean titers (GMTs) ranging from 184 (95% confidence interval [CI]: 127-266) to 380 (95% CI: 272-531). At 28 days post-dose 1, anti-RSV NAb GMTs in vaccine recipients ranged from 893 (95% CI: 702-1,136) to 1,602 (95% CI: 1,243-2,064). No booster effect was observed, but immune responses were maintained above pre-vaccination levels for six months post-dose 1. Ratios of RSV F total binding antibodies fold changes to NAb fold changes ranged from 2.79 to 4.12 at 28 days post-dose 1. The impact of the adjuvant was limited. CONCLUSIONS: A single dose of each formulation of RSV subunit F vaccine was well-tolerated and enhanced preexisting NAb titers through six months of follow-up.

A multiresolution processing method for contrast enhancement in portal imaging.

Portal images have a unique feature among the imaging modalities used in radiotherapy: they provide direct visualization of the irradiated volumes. However, contrast and spatial resolution are strongly limited due to the high energy of the radiation sources. Because of this, imaging modalities using x-ray energy beams have gained importance in the verification of patient positioning, replacing portal imaging. The purpose of this work was to develop a method for the enhancement of local contrast in portal images. The method operates in the sub-bands of a wavelet decomposition of the image, re-scaling them in such a way that coefficients in the high and medium resolution sub-bands are amplified-an approach totally different from those operating on the image histogram, widely used nowadays. Portal images of an anthropomorphic phantom were acquired in an electronic portal imaging device. Then, different re-scaling strategies were investigated, studying the effects of the scaling parameters on the enhanced images. Also, the effect of using different types of transform was studied. Finally, the implemented methods were combined with histogram equalization methods like the contrast limited adaptive histogram equalization, and these combinations were compared. Uniform amplification of the detail sub-bands shows the best results in contrast enhancement. On the other hand, linear re-escalation of the high resolution sub-bands increases the visibility of fine detail in the images, at the expense of an increase in noise levels. Also, since processing is applied only to detail sub-bands, not to the approximation, the mean gray level of the image is minimally modified and no further display adjustments are required. It is shown that re-escalation of the detail sub-bands of portal images can be used as an efficient method for the enhancement of both the local contrast and the resolution of these images.

Denoising portal images by minimizing the SURE estimator on a parameterized family of shrinkage functions.

The number of verification portal images in radiotherapy has increased in the last years. On the other hand, radiation delivered during imaging is not confined to the treatment volumes, but also affects the surrounding organs and tissues. In order to reduce the overall radiation dose due to imaging, one approach would be to reduce the dose per image, but noise would increase and the quality of portal images would reduce. The limited quality of portal images makes it difficult to propose a reduction of dose if there is no way to effectively reduce noise. Denoising algorithms could be the solution if the quality of the restored image can match the image obtained with a standard dose. In this work the statistical properties of noise in a portal imaging system and the statistical properties of portal images are used to develop an efficient denoising method. The result is a method that minimizes the Stein's unbiased risk estimator (SURE) in the image domain over a parametric family of shrinkage functions operating in the wavelet domain. The presented denoising method shows a better performance than the adaptive Wiener estimator for different portal images and noise energies.

Characterization of noise and digitizer response variability in radiochromic film dosimetry. Impact on treatment verification.

PURPOSE: To study how noise and scanner response variability affect radiochromic film dosimetry. METHODS: Five treatment plans were analyzed in this work with two different multichannel protocols: the multichannel algorithm of Mayer et al. and the efficient protocol of Lewis et al. RESULTS AND CONCLUSION: The multichannel protocol of Mayer et al. is not able to compensate variability in scanner response, which is an important issue for radiochromic film dosimetry. The efficient protocol compensates variations of scanner response, so dose values and gamma scores become more accurate and reproducible. The compensation of digitizer scan variability of the efficient protocol, together with time averaging improve radiochromic film dosimetry. Noise is related to selected resolution in the scanner, our results show that if high resolution measurements are required, de-noising should be considered.

Portal imaging: Performance improvement in noise reduction by means of wavelet processing.

This paper discusses the suitability, in terms of noise reduction, of various methods which can be applied to an image type often used in radiation therapy: the portal image. Among these methods, the analysis focuses on those operating in the wavelet domain. Wavelet-based methods tested on natural images--such as the thresholding of the wavelet coefficients, the minimization of the Stein unbiased risk estimator on a linear expansion of thresholds (SURE-LET), and the Bayes least-squares method using as a prior a Gaussian scale mixture (BLS-GSM method)--are compared with other methods that operate on the image domain--an adaptive Wiener filter and a nonlocal mean filter (NLM). For the assessment of the performance, the peak signal-to-noise ratio (PSNR), the structural similarity index (SSIM), the Pearson correlation coefficient, and the Spearman rank correlation (ρ) coefficient are used. The performance of the wavelet filters and the NLM method are similar, but wavelet filters outperform the Wiener filter in terms of portal image denoising. It is shown how BLS-GSM and NLM filters produce the smoothest image, while keeping soft-tissue and bone contrast. As for the computational cost, filters using a decimated wavelet transform (decimated thresholding and SURE-LET) turn out to be the most efficient, with calculation times around 1 s.

Small fields measurements with radiochromic films.

The small fields in radiotherapy are widely used due to the development of techniques such as intensity-modulated radiotherapy and stereotactic radio surgery. The measurement of the dose distributions for small fields is a challenge. A perfect dosimeter should be independent of the radiation energy and the dose rate and should have a negligible volume effect. The radiochromic (RC) film characteristics fit well to these requirements. However, the response of RC films and their digitizing processes present a significant spatial inhomogeneity problem. The present work uses a method for two-dimensional (2D) measurement with RC films based on the reduction of the spatial inhomogeneity of both the film and the film digitizing process. By means of registering and averaging several measurements of the same field, the inhomogeneities are mostly canceled. Measurements of output factors (OFs), dose profiles (in-plane and cross-plane), and 2D dose distributions are presented. The field sizes investigated are 0.5 × 0.5 cm(2), 0.7 × 0.7 cm(2), 1 × 1 cm(2), 2 × 2 cm(2), 3 × 3 cm(2), 6 × 6 cm(2), and 10 × 10 cm(2) for 6 and 15 MV photon beams. The OFs measured with the RC film are compared with the measurements carried out with a PinPoint ionization chamber (IC) and a Semiflex IC, while the measured transversal dose profiles were compared with Monte Carlo simulations. The results obtained for the OFs measurements show a good agreement with the values obtained from RC films and the PinPoint and Semiflex chambers when the field size is greater or equal than 2 × 2 cm(2). These agreements give confidence on the accuracy of the method as well as on the results obtained for smaller fields. Also, good agreement was found between the measured profiles and the Monte Carlo calculated profiles for the field size of 1 × 1 cm(2). We expect, therefore, that the presented method can be used to perform accurate measurements of small fields.

Statistical characterization of portal images and noise from portal imaging systems.

In this paper, we consider the statistical characteristics of the so-called portal images, which are acquired prior to the radiotherapy treatment, as well as the noise that present the portal imaging systems, in order to analyze whether the well-known noise and image features in other image modalities, such as natural image, can be found in the portal imaging modality. The study is carried out in the spatial image domain, in the Fourier domain, and finally in the wavelet domain. The probability density of the noise in the spatial image domain, the power spectral densities of the image and noise, and the marginal, joint, and conditional statistical distributions of the wavelet coefficients are estimated. Moreover, the statistical dependencies between noise and signal are investigated. The obtained results are compared with practical and useful references, like the characteristics of the natural image and the white noise. Finally, we discuss the implication of the results obtained in several noise reduction methods that operate in the wavelet domain.