A Live Attenuated COVID-19 Candidate Vaccine for Children: Protection against SARS-CoV-2 Challenge in Hamsters.

Children are at risk of infection from severe acute respiratory syndrome coronavirus-2 virus (SARS-CoV-2) resulting in coronavirus disease (COVID-19) and its more severe forms. New-born infants are expected to receive short-term protection from passively transferred maternal antibodies from their mothers who are immunized with first-generation COVID-19 vaccines. Passively transferred antibodies are expected to wane within first 6 months of infant's life, leaving them vulnerable to COVID-19. Live attenuated vaccines, unlike inactivated or viral-protein-based vaccines, offer broader immune engagement. Given effectiveness of live attenuated vaccines in controlling infectious diseases such as mumps, measles and rubella, we undertook development of a live attenuated COVID-19 vaccine with an aim to vaccinate children beyond 6 months of age. An attenuated vaccine candidate (dCoV), engineered to express sub-optimal codons and deleted polybasic furin cleavage sites in the spike protein of the SARS-CoV-2 WA/1 strain, was developed and tested in hamsters. Hamsters immunized with dCoV via intranasal or intramuscular routes induced high levels of neutralizing antibodies and exhibited complete protection against the SARS-CoV-2 wild-type isolates, i.e., the Wuhan-like (USA-WA1/2020) and Delta variants (B.1.617.2) in a challenge study. In addition, the dCoV formulated with the marketed measles-rubella (MR) vaccine, designated as MR-dCoV, administered to hamsters via intramuscular route, also protected against both SARS-CoV-2 challenges, and dCoV did not interfere with the MR vaccine-mediated immune response. The safety and efficacy of the dCoV and the MR-dCoV against both variants of SARS-CoV-2 opens the possibility of early immunization in children without an additional injection.

Impact of Dimensionality Reduction on Outlier Detection: an Empirical Study.

Outlier detection is a fundamental data analytics technique often used for many security applications. Numerous outlier detection techniques exist, and in most cases are used to directly identify outliers without any interaction. Typically the underlying data used is often high dimensional and complex. Even though outliers may be identified, since humans can easily grasp low dimensional spaces, it is difficult for a security expert to understand/visualize why a particular event or record has been identified as an outlier. In this paper we study the extent to which outlier detection techniques work in smaller dimensions and how well dimensional reduction techniques still enable accurate detection of outliers. This can help us to understand the extent to which data can be visualized while still retaining the intrinsic outlyingness of the outliers.

Unsupervised high-intensity interval training improves glycaemic control but not cardiovascular autonomic function in type 2 diabetes patients: A randomised controlled trial.

BACKGROUND: This is the first randomised controlled trial to assess the impact of unsupervised high-intensity interval training on cardiovascular autonomic function in adults with type 2 diabetes. METHODS: A total of 22 individuals with type 2 diabetes (age 60 ± 2 years, 17 males) lay in a supine position for 20 min for evaluation of cardiovascular autonomic function, which included (1) time domain measures of heart rate variability, (2) frequency domain measures of heart rate variability and blood pressure variability and (3) baroreflex receptor sensitivity. Participants were randomised into 12 weeks of high-intensity interval training (3 sessions/week) or standard care control group. RESULTS: After 12 weeks, the between-group change in HbA1c (%) was significant (high-intensity interval training: 7.13 ± 0.31 to 6.87 ± 0.29 vs Control: 7.18 ± 0.17 to 7.36 ± 0.21, p = 0.03). There were no significant changes in measures of heart rate variability; R-R interval (ms) (high-intensity interval training: 954 ± 49 to 973 ± 53 vs Control: 920 ± 6 to 930 ± 32, p = 0.672), low frequency/high frequency (high-intensity interval training: 0.90 ± 0.21 to 0.73 ± 0.07 vs Control: 1.20 ± 0.29 to 1.00 ± 0.17, p = 0.203), or blood pressure variability; systolic blood pressure low frequency/high frequency (high-intensity interval training: 0.86 ± 0.21 to 0.73 ± 0.10 vs Control: 1.06 ± 0.26 to 0.91 ± 0.14, p = 0.169). At baseline, HbA1c was negatively correlated with baroreflex receptor sensitivity ( r = -0.592, p < 0.01). CONCLUSION: High-intensity interval training improves glycaemic control but has limited effect on cardiovascular autonomic regulation in patients with type 2 diabetes.

Ultraviolet-C irradiation for inactivation of viruses in foetal bovine serum.

Foetal Bovine Serum (FBS) and porcine trypsin are one of the essential raw materials used in the manufacturing of cell culture based viral vaccines. Being from animal origin, these raw materials can potentially contaminate the final product by known or unknown adventitious agents. The issue is more serious in case of live attenuated viral vaccines, where there is no inactivation step which can take care of such adventitious agents. It is essential to design production processes which can offer maximum viral clearance potential for animal origin products. Ultraviolet-C irradiation is known to inactivate various adventitious viral agents; however there are limited studies on ultraviolet inactivation of viruses in liquid media. We obtained a recently developed UVivatec ultraviolet-C (UV-C) irradiation based viral clearance system for evaluating its efficacy to inactivate selected model viruses. This system has a unique design with spiral path of liquid allowing maximum exposure to UV-C light of a short wavelength of 254 nm. Five live attenuated vaccine viruses and four other model viruses were spiked in tissue culture media and exposed to UV-C irradiation. The pre and post UV-C irradiation samples were analyzed for virus content to find out the extent of inactivation of various viruses. These experiments showed substantial log reduction for the majority of the viruses with few exceptions based on the characteristics of these viruses. Having known the effect of UV irradiation on protein structure, we also evaluated the post irradiation samples of culture media for growth promoting properties using one of the most fastidious human diploid cells (MRC-5). UV-C exposure did not show any notable impact on the nutritional properties of culture media. The use of an UV-C irradiation based system is considered to be promising approach to mitigate the risk of adventitious agents in cell culture media arising through animal derived products.

Breast lesion detection and characterization with 3D features.

Automated Breast Ultrasound (ABUS) is highly effective as breast cancer screening adjunct technology. Automation can greatly enhance the efficiency of the clinician sifting through the quantum of data in ABUS volumes to spot lesions. We have implemented a fully automatic generic algorithm pipeline for detection and characterization of lesions on such 3D volumes. We compare a wide range of features for region description on their effectiveness at the dual goals of lesion detection and characterization. On multiple feature images, we compute region descriptors at lesion candidate locations obviating the need for explicit lesion segmentation. We use Random Forests classifier to evaluate candidate region descriptors for lesion detection. Further, we categorize true lesions as Malignant or other masses (e.g. Cysts). Over a database of 145 volumes, with 36 biopsy verified lesions, we achieved Area Under the Curve (AUC) values of 92.6% for lesion detection and 89% for lesion characterization.

Improved mass detection in 3D automated breast ultrasound using region based features and multi-view information.

Breast cancer is one of the leading causes of cancer death for women. Early detection of breast cancer is crucial for reducing mortality rates and improving prognosis of patients. Recently, 3D automated breast ultrasound (ABUS) has gained increasing attentions for reducing subjectivity, operator-dependence, and providing 3D context of the whole breast. In this work, we propose a breast mass detection algorithm improving voxel-based detection results by incorporating 3D region-based features and multi-view information in 3D ABUS images. Based on the candidate mass regions produced by voxel-based method, our proposed approach further improves the detection results with three major steps: 1) 3D mass segmentation in geodesic active contours framework with edge points obtained from directional searching; 2) region-based single-view and multi-view feature extraction; 3) support vector machine (SVM) classification to discriminate candidate regions as breast masses or normal background tissues. 22 patients including 51 3D ABUS volumes with 44 breast masses were used for evaluation. The proposed approach reached sensitivities of 95%, 90%, and 70% with averaged 4.3, 3.8, and 1.6 false positives per volume, respectively. The results also indicate that the multi-view information plays an important role in false positive reduction in 3D breast mass detection.

Safety and immunogenicity of dry powder measles vaccine administered by inhalation: a randomized controlled Phase I clinical trial.

BACKGROUND: Measles is a highly infectious respiratory disease which causes 122,000 deaths annually. Although measles vaccine is extremely safe and effective, vaccine coverage could be improved by a vaccine that is more easily administered and transported. We developed an inhalable dry powder measles vaccine (MVDP) and two delivery devices, and demonstrated safety, immunogenicity, and efficacy of the vaccine in preclinical studies. Here we report the first clinical trial of MVDP delivered by inhalation. METHODOLOGY: Sixty adult males aged 18 to 45 years, seropositive for measles antibody, were enrolled in this controlled Phase I clinical study. Subjects were randomly assigned in 1:1:1 ratio to receive either MVDP by Puffhaler(®) or by Solovent™ devices or the licensed subcutaneous measles vaccine. Adverse events (AEs) were recorded with diary cards until day 28 post-vaccination and subjects were followed for 180 days post-vaccination to assess potential serious long term adverse events. Measles antibody was measured 7 days before vaccination and at days 21 and 77 after vaccination by ELISA and a plaque reduction neutralization test. RESULTS: All subjects completed the study according to protocol. Most subjects had high levels of baseline measles antibody. No adverse events were reported. MVDP produced serologic responses similar to subcutaneous vaccination. CONCLUSIONS: MVDP was well tolerated in all subjects. Most subjects had high baseline measles antibody titer which limited ability to measure the serologic responses, and may have limited the adverse events following vaccination. Additional studies in subjects without pre-existing measles antibody are needed to further elucidate the safety and immunogenicity of MVDP.

A pandemic influenza vaccine in India: from strain to sale within 12 months.

In the event of a highly pathogenic influenza pandemic, the Indian subcontinent would need 1.2 billion doses of vaccine to immunize its entire population, double if two doses were required to assure immunity. Serum Institute of India Limited (SII) thus became one of six initial grantees of the World Health Organization (WHO) technology transfer initiative to create capacity in developing countries to manufacture H5N1 pandemic influenza vaccine. At the outbreak of the A(H1N1) 2009 influenza pandemic, experience gained from the H5N1 project was used to develop a live attenuated influenza vaccine (LAIV), since this was the only option for the level of surge capacity required for a large-scale immunization campaign in India. SII took <12 months to develop and market its LAIV intranasal vaccine from receipt of the seed strain from WHO. As of November 2010, over 2.5 million persons have been vaccinated with Nasovac(®) with no serious adverse reactions or vaccine failure after 3 months' post-marketing surveillance. The product has been submitted for prequalification by WHO for purchase by United Nations agencies. In parallel, SII also developed an inactivated influenza vaccine, and is currently looking to ensure the sustainability of its influenza vaccine manufacturing capacity.