Abstract Q-fever is a flu-like illness caused by Coxiella burnetii ( Cb ), a highly infectious intracellular bacterium. There is an unmet need for a safe and effective vaccine for Q-fever. Correlates of immune protection to Cb infection are limited. We proposed that analysis by longitudinal high dimensional immune (HDI) profiling using mass cytometry combined with other measures of vaccination and protection could be used to identify novel correlates of effective vaccination and control of Cb infection. Using a vaccine-challenge model in HLA-DR transgenic mice, we demonstrated significant alterations in circulating T-cell and innate immune populations that distinguished vaccinated from naïve mice within 10 days, and persisted until at least 35 days post-vaccination. Following challenge, vaccinated mice exhibited reduced bacterial burden and splenomegaly, along with distinct effector T-cell and monocyte profiles. Correlation of HDI data to serological and pathological measurements was performed. Our data indicate a Th1-biased response to Cb , consistent with previous reports, and identify Ly6C, CD73, and T-bet expression in T-cell, NK-cell, and monocytic populations as distinguishing features between vaccinated and naïve mice. This study refines the understanding of the integrated immune response to Cb vaccine and challenge, which can inform the assessment of candidate vaccines for Cb .
Vaccines have been invaluable for global health, saving lives and reducing healthcare costs, while also raising the quality of human life. However, newly emerging infectious diseases (EID) and more well-established tropical disease pathogens present complex challenges to vaccine developers; in particular, neglected tropical diseases, which are most prevalent among the world's poorest, include many pathogens with large sizes, multistage life cycles and a variety of nonhuman vectors. EID such as MERS-CoV and H7N9 are highly pathogenic for humans. For many of these pathogens, while their genomes are available, immune correlates of protection are currently unknown. These complexities make developing vaccines for EID and neglected tropical diseases all the more difficult. In this review, we describe the implementation of an immunoinformatics-driven approach to systematically search for key determinants of immunity in newly available genome sequence data and design vaccines. This approach holds promise for the development of 21st century vaccines, improving human health everywhere.
Monoclonal antibodies have proved to be extremely valuable additions to conventional treatment for rheumatic diseases. However, despite the general trend towards "humanisation", these drugs remain immunogenic in clinical settings, baffling drug developers. In principle, humanised and fully human monoclonal antibodies are "self" immunoglobulins and should be tolerated. In this overview, the factors that may influence this process, the nature of immunogenicity and methods to analyse and modify potential immunogenicity are discussed. Finally, novel approaches to "re-induce" immunological tolerance to these proteins, including gene therapy and the recognition of unique regulatory epitopes, are outlined.
T lymphocytes play a major role in the recognition and subsequent elimination of tumors and intracellular pathogens. Induction of epitope-specific T cell responses can help in the clearance of diseases for which no conventional vaccines exist. However, the lack of simple methods to identify relevant T cell epitopes, the high mutation rate of many pathogens, and HLA polymorphism have made the development of efficient T cell epitope-based, or “epitope-driven” vaccines difficult to achieve. Our research over the past several years has applied bioinformatics tools in conjunction with T cell assays to identify naturally processed putative T cell epitopes from several pathogens. This strategy willaccelerate the development of new generation T cell epitopebased vaccines against various pathogens including viruses such as HIV and WNV, bacteria such as M.tb ., and parasites such as plasmodium. This chapter will review the use of a bioinformatics-based approach to identify putative T cell epitopes. It will summarize the current state of knowledge regarding T cell-epitope-based vaccines and discuss several ways to improve their efficacy.
We conducted a retrospective cohort study to evaluate changes in metabolic biomarkers among participants in Bridging the [Health Equity] Gap (BTG), a free program run by Clínica Esperanza/Hope Clinic (CEHC) for Spanish-speaking immigrants without health insurance in Rhode Island. From July 2019 through June 2021, 471 people volunteered to participate in the BTG program. Participants enrolled in lifestyle change classes and visited quarterly with health care providers. We reviewed medical records to collect data on blood glucose, total cholesterol, hemoglobin A1c (HbA1c), and systolic and diastolic blood pressure at baseline and at 6, 12, 18, and 21 months after enrollment. We used paired t tests to identify changes in measurements and conducted a regression analysis to analyze trends in longitudinal patient outcomes. From baseline to 6-month follow-up, we observed significant decreases in all participants' mean HbA1c (-0.71%), systolic (-5 mm Hg), and diastolic blood pressure (-2 mm Hg). At 12 months, significant decreases in mean HbA1c persisted among participants with diabetes and prediabetes (-1.07%). At 12 months, participants with mean systolic blood pressure >120 mm Hg also had significant decreases in mean systolic blood pressure (-9 mm Hg), and patients with diastolic blood pressure >80 mm Hg had significant decreases in mean diastolic blood pressure (-9 mm Hg). Local population-level surges in COVID-19 due to Delta and Omicron variants were associated with increases in HbA1c and blood glucose measurements above trendlines. The BTG program demonstrated resilience in supporting improvement in the metabolic biomarkers of participants, despite disruptions caused by the COVID-19 pandemic, the continued engagement of participants in self-care despite limited health care access, and underscores the positive role of free clinics among low-income, Spanish-speaking immigrants.
Biologics developers are moving beyond antibodies for delivery of a wide range of therapeutic interventions. These non-antibody modalities are often based on ‘natural’ protein scaffolds that are modified to deliver bioactive sequences. Both human-derived and non-human-sourced scaffold proteins have been developed. New types of “non-antibody” scaffolds are still being discovered, as they offer attractive alternatives to monoclonals due to their smaller size, improved stability, and ease of synthesis. They are believed to have low immunogenic potential. However, while several human-sourced protein scaffolds have not been immunogenic in clinical studies, this may not predict their overall performance in other therapeutic applications. A preliminary evaluation of their potential for immunogenicity is warranted. Immunogenicity risk potential has been clearly linked to the presence of T “helper” epitopes in the sequence of biologic therapeutics. In addition, tolerogenic epitopes are present in some human proteins and may decrease their immunogenic potential. While the detailed sequences of many non-antibody scaffold therapeutic candidates remain unpublished, their backbone sequences are available for review and analysis. We assessed 12 example non-antibody scaffold backbone sequences using our epitope-mapping tools (EpiMatrix) for this perspective. Based on EpiMatrix scoring, their HLA DRB1-restricted T cell epitope content appears to be lower than the average protein, and sequences that may act as tolerogenic epitopes are present in selected human-derived scaffolds. Assessing the potential immunogenicity of scaffold proteins regarding self and non-self T cell epitopes may be of use for drug developers and clinicians, as these exciting new non-antibody molecules begin to emerge from the preclinical pipeline into clinical use.
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