A Method for Individualizing the Prediction of Immunogenicity of Protein Vaccines and Biologic Therapeutics: Individualized T Cell Epitope Measure (iTEM)

The promise of pharmacogenomics depends on advancing predictive medicine. To address this need in the area of immunology, we developed the individualized T cell epitope measure (iTEM) tool to estimate an individual's T cell response to a protein antigen based on HLA binding predictions. In this study, we validated prospective iTEM predictions using data from in vitro and in vivo studies. We used a mathematical formula that converts DRB1* allele binding predictions generated by EpiMatrix, an epitope-mapping tool, into an allele-specific scoring system. We then demonstrated that iTEM can be used to define an HLA binding threshold above which immune response is likely and below which immune response is likely to be absent. iTEM's predictive power was strongest when the immune response is focused, such as in subunit vaccination and administration of protein therapeutics. iTEM may be a useful tool for clinical trial design and preclinical evaluation of vaccines and protein therapeutics

Physical Therapy for Hospitalized COVID-19 Patients in Isolation: Feasibility and pilot implementation of telehealth for delivering individualized therapy.

Objective To optimize the ability of hospitalized patients isolated due to COVID-19 to participate in physical therapy. Design This was a prospective, quality improvement trial of the feasibility and acceptability of a hybrid in-person and telerehabilitation platform to deliver physical therapy to hospitalized adults. Setting Inpatient wards of a tertiary care, multi-specialty academic medical center in the greater New York City metropolitan area. Participants A convenience sample of 39 COVID-19+ adults, mean age 57.3 years, 69% male, all previously community dwelling agreed to participate in a combination of in-person and telerehabilitation sessions (TR). Intervention Initial in-person evaluation by physical therapist followed by twice daily PT sessions, one in-person and one via a telehealth platform meeting Health Insurance Portability and Accountability Act (HIPAA) confidentiality requirements. The communication platform was downloaded to each participant\u27s personal smart device to establish audiovisual contact with the Physical Therapist. Measures The 6-clicks Activity Measure for Post-Acute Care (AM-PAC) was used to score self-reported functional status pre-morbidly by, and by the therapist at baseline and discharge. Results Functional status measured by AM-PAC 6-clicks demonstrated improvement from admission to discharge. Barriers to participation were identified and strategies are planned to facilitate use of the platform in future. Conclusions A consistent and structured protocol for engaging patient participation in PT delivered via a telehealth platform was successfully developed. A process was put in place to allow for further development, recruitment and testing in a randomized trial

T cell epitope: Friend or Foe? Immunogenicity of biologics in context

Like vaccines, biologic proteins can be very immunogenic for reasons including route of administration, dose frequency and the underlying antigenicity of the therapeutic protein. Because the impact of immunogenicity can be quite severe, regulatory agencies are developing risk-based guidelines for immunogenicity screening. T cell epitopes are at the root of the immunogenicity issue. Through their presentation to T cells, they activate the process of anti-drug antibody development. Preclinical screening for T cell epitopes can be performed in silico, followed by in vitro and in vivo validation. Importantly, screening for immunogenicity is complicated by the discovery of regulatory T cell epitopes, which suggests that immunogenicity testing must now take regulatory T cells into consideration. In this review, we address the application of computational tools for preclinical immunogenicity assessment, the implication of the discovery of regulatory T cell epitopes, and experimental validation of those assessments

Low immunogenicity predicted for emerging avian-origin H7N9

A new avian-origin influenza virus emerged near Shanghai in February 2013, and by the beginning of May it had caused over 130 human infections and 36 deaths. Human-to-human transmission of avian-origin H7N9 influenza A has been limited to a few family clusters, but the high mortality rate (27%) associated with human infection has raised concern about the potential for this virus to become a significant human pathogen. European, American, and Asian vaccine companies have already initiated the process of cloning H7 antigens such as hemagglutinin (HA) into standardized vaccine production vehicles. Unfortunately, previous H7 HA-containing vaccines have been poorly immunogenic. We used well-established immunoinformatics tools to analyze the H7N9 protein sequences and compare their T cell epitope content to other circulating influenza A strains as a means of estimating the immunogenic potential of the new influenza antigen. We found that the HA proteins derived from closely related human-derived H7N9 strains contain fewer T cell epitopes than other recently circulating strains of influenza, and that conservation of T cell epitopes with other strains of influenza was very limited. Here, we provide a detailed accounting of the type and location of T cell epitopes contained in H7N9 and their conservation in other H7 and circulating (A/California/07/2009, A/Victoria/361/2011, and A/Texas/50/2012) influenza A strains. Based on this analysis, avian-origin H7N9 2013 appears to be a “stealth” virus, capable of evading human cellular and humoral immune response. Should H7N9 develop pandemic potential, this analysis predicts that novel strategies for improving vaccine immunogenicity for this unique low-immunogenicity strain of avian-origin influenza will be urgently needed

Immunogenic Consensus Sequence T Helper Epitopes for a Pan-Burkholderia Biodefense Vaccine

Background: Biodefense vaccines against Category B bioterror agents Burkholderia pseudomallei (BPM) and Burkholderia mallei (BM) are needed, as they are both easily accessible to terrorists and have strong weaponization potential. Burkholderia cepaciae (BC), a related pathogen, causes chronic lung infections in cystic fibrosis patients. Since BPM, BM and BC are all intracellular bacteria, they are excellent targets for T cell-based vaccines. However, the sheer volume of available genomic data requires the aid of immunoinformatics for vaccine design. Using EpiMatrix, ClustiMer and EpiAssembler, a set of immunoinformatic vac-cine design tools, we screened the 31 available Burkholderia genomes and performed initial tests of our selections that are candidates for an epitope-based multi-pathogen vaccine against Burkholderia species. Results: Immunoinformatics analysis of 31 Burkholderia genomes yielded 350,004 9-mer candidate vaccine peptides of which 133,469 had perfect conservation across the 10 BM genomes, 175,722 had per-fect conservation across the 11 BPM genomes and 40,813 had perfect conservation across the 10 BC genomes. Further screening with EpiMatrix yielded 54,010 high-scoring Class II epitopes; these were assembled into 2,880 longer highly conserved ‘immunogenic consensus sequence’ T helper epitopes. 100% of the peptides bound to at least one HLA class II allele in vitro, 92.7% bound to at least two alleles, 82.9% to three, and 75.6% of the binding results were consistent with the immunoinformatics analysis. Conclusions: Our results show it is possible to rapidly identify promiscuous T helper epitopes conserved across multiple Burkholderia species and test their binding to HLA ligands in vitro. The next step in our process will be to test the epitopes ex vivo using peripheral leukocytes from BC, BPM infected humans and for immunogenicity in human HLA transgenic mice. We expect that this approach will lead to development of a licensable, pan-Burkholderia biodefense vaccine

Signal and noise simulation of CUORE bolometric detectors

Bolometric detectors are used in particle physics experiments to search for rare processes, such as neutrinoless double beta decay and dark matter interactions. By operating at cryogenic temperatures, they are able to detect particle energies from a few keV up to several MeV, measuring the temperature rise produced by the energy released. This work focusses on the bolometers of the CUORE experiment, which are made of TeO$_2$ crystals. The response of these detectors is nonlinear with energy and changes with the operating temperature. The noise depends on the working conditions and significantly affects the energy resolution and the detection performances at low energies. We present a software tool to simulate signal and noise of CUORE-like bolometers, including effects generated by operating temperature drifts, nonlinearities and pileups. The simulations agree well with data.Comment: Fixed a typo. Two small changes in the text at page

Universal H1N1 influenza vaccine development

Immune responses to cross-conserved T cell epitopes in novel H1N1 influenza may explain reports of diminished influenza-like illnesses and confirmed infection among older adults, in the absence of cross-reactive humoral immunity, during the 2009 pandemic. These cross-conserved epitopes may prove useful for the development of a universal H1N1 influenza vaccine, therefore, we set out to identify and characterize cross-conserved H1N1 T cell epitopes. An immunoinformatic analysis was conducted using all available pandemic and pre-pandemic HA-H1 and NA-N1 sequences dating back to 1980. Using an approach that balances potential for immunogenicity with conservation, we derived 13 HA and four NA immunogenic consensus sequences (ICS) from a comprehensive analysis of 5 738 HA-H1 and 5 396 NA-N1 sequences. These epitopes were selected because their combined epitope content is representative of greater than 84% of pre-pandemic and pandemic H1N1 influenza strains, their predicted immunogenicity (EpiMatrix) scores were greater than or equal to the 95th percentile of all comparable epitopes, and they were also predicted to be presented by more than four HLA class II archetypal alleles. We confirmed the ability of these peptides to bind in HLA binding assays and to stimulate interferon-γ production in human peripheral blood mononuclear cell cultures. These studies support the selection of the ICS as components of potential group-common H1N1 vaccine candidates and the application of this universal influenza vaccine development approach to other influenza subtypes