ALTERED FEATURES of B and T CELL RESPONSES to BNT162 VACCINE in HEMODIALYSIS PATIENTS

Background: People receiving hemodialysis (HD) are highly vulnerable to SARS-CoV-2 infection and develop lower antibody responses to SARS-CoV-2 mRNA vaccines. However, the underlying immune defects are poorly understood. We compared immune responses of 27 HD patients with 22 health care workers (HCW) before and up to 4 months after 2 doses of BNT162 SARS-CoV-2 vaccination. All participants were confirmed to be SARS-CoV-2 naïve. Methods: We profiled B cells, CD4 T cells, CD8 T cells and humoral responses and examined associations between these arms of immunity. We used high-parameter flow cytometry to study: i) receptor binding domain (RBD)-specific B cells;ii) the phenotype of Spike (S)-specific CD4 and CD8 T cells identified by an activation-induced marker (AIM) assay;iii) effector functions of S-specific CD4 and CD8 T cells by intracellular staining (ICS). We measured humoral responses by ELISA RBD. Results: In each cohort, two vaccine doses enhanced RBD-specific B cell responses, with a significantly greater increase after the second dose (V2 than after the first dose (V1). Their magnitude was significantly lower in HD than in HCW at V1 (p=0.002) and V2 (p=0.002), which was consistent with the detection of lower anti-RBD IgG antibody levels at the same time points (V1: p<0.001;V2: p<0.001). The subsequent rates of B cell decline were similar in HD and HCW. As CD4 help is critical for B cell and CD8 T cell immunity, we compared Spike (S)-specific T cells responses between cohorts. While we observed no significant quantitative difference in the magnitude of vaccine-specific CD4 T cells between HD and HCW at V2, phenotypic and functional Thelper profiles differed significantly. The frequency of vaccine-specific CXCR3+ Th1 CD4 T cells was significantly increased in HD compared to HCW (p=0.008), and TNFα+ CD4 T cell responses were elevated in HD (p=0.01). In contrast to CD4 T cells, S-specific CD8 T cell responses were quantitatively reduced in HD compared to HCW after each dose (V1: p<0.001;V2: p<0.001). Conclusion: People on HD develop poor B cell and CD8 T cell responses after SARS-CoV-2 mRNA vaccination. These defects are associated with a skewed differentiation of vaccine-specific CD4 T cells toward CXCR3+ and TNFα+ Th1-like profiles, and probable altered crosstalk between Thelper and B cells. Further study is needed to determine if impaired B and T cell vaccine immunity in addition to defective antibody responses increases vulnerability of HD patients to breakthrough COVID-19 infection.

TEMPORAL ASSOCIATIONS of B and T CELL IMMUNITY in A 16-WEEK INTERVAL BNT162b2 REGIMEN

Background: Spacing of the BNT162b2 mRNA doses beyond the standard 3-week interval raised concerns about vaccine efficacy. We longitudinally analyzed B cell, T cell and humoral responses to two BNT162b2 mRNA doses administered 16 weeks apart in 43 SARS-CoV-2 naïve and previously-infected (PI) donors. We examined blood samples at five time points from baseline to 4 months post second dose. Methods: We used high-parameter flow cytometry to study: i) receptor binding domain (RBD)-specific B cells;ii) Spike (S)-specific CD4 and CD8 T cells by activation-induced marker (AIM) assay;iii) S-specific CD4 and CD8 T cells by intracellular staining (ICS) assay. We measured humoral responses by ELISA, neutralization and ADCC assays. We did supervised and unsupervised (FlowSOM) analyses of B and T cell subsets, and temporal association analyses. Results: We observed partial attrition of B and T cell responses between doses at a memory time point 12 weeks post first dose. RBD-specific B cell kinetics differed between cohorts: the first dose led to their robust increase in PI but small magnitude in naïve. The second dose had little effect in PI but briskly expanded RBD-specific B cells in naïve, leading to convergence between cohorts. Robust T cell responses, with a dominance of CD4 over CD8 responses, were universally induced and did not significantly differ in magnitude after either dose, although there was a trend for a gain in CD8 responses after the second dose in naïve. Unsupervised and supervised analyses of S-specific CD4 T cells showed that the first dose was sufficient to generate highly diverse CD4 subsets, including robust populations of follicular T helper cells. The second dose did not elicit new subsets but lead to convergent phenotypic and functional profiles between PI and naïve with qualitative shifts. Integrated analyses of antigen-specific responses showed immune component-specific associations over-time, with early CD4 responses post-first dose (but not at late time points) strongly correlating with B cell responses after the second dose. In contrast, CD8 responses post second dose correlated with CD4 responses at the same time point. Conclusion: The 16-week interval schedule is associated with robust, multi-faceted recall cellular responses after the second dose, consistent with highly functional immune memory. The early induction of robust CD4 responses and their associations with longer-term B cell and humoral immunity support their central role in the efficacy of this vaccine regimen.

Lithium salts as a treatment for COVID-19: Pre-clinical outcomes.

INTRODUCTION: Identifying effective drugs for Coronavirus disease 2019 (COVID-19) is urgently needed. An efficient approach is to evaluate whether existing approved drugs have anti-SARS-CoV-2 effects. The antiviral properties of lithium salts have been studied for many years. Their anti-inflammatory and immune-potentiating effects result from the inhibition of glycogen synthase kinase-3. AIMS: To obtain pre-clinical evidence on the safety and therapeutic effects of lithium salts in the treatment of COVID-19. RESULTS: Six different concentrations of lithium, ranging 2-12 mmol/L, were evaluated. Lithium inhibited the replication of SARS-CoV-2 virus in a dose-dependent manner with an IC50 value of 4 mmol/L. Lithium-treated wells showed a significantly higher percentage of monolayer conservation than viral control, particularly at concentrations higher than 6 mmol/L, verified through microscopic observation, the neutral red assay, and the determination of N protein in the supernatants of treated wells. Hamsters treated with lithium showed less intense disease with fewer signs. No lithium-related mortality or overt signs of toxicity were observed during the experiment. A trend of decreasing viral load in nasopharyngeal swabs and lungs was observed in treated hamsters compared to controls. CONCLUSIONS: These results provide pre-clinical evidence of the antiviral and immunotherapeutic effects of lithium against SARS-CoV-2, which supports an advance to clinical trials on COVID-19's patients.

We Are Not Pontius Pilate: Acknowledging Ethics and Policy

A new AI system is being developed to optimize vaccination strategies based on the structure and shape of a community's social contact network. The technology is minimally constrained and not hound by preconceived notions or human biases. With this come novel outside the box strategies;however, the system is only capable of optimizing what it is instructed to optimize, and does not consider any ethical or political concerns. With the growing concern for systematic discrimination as a result of artificial intelligence, we acknowledge a number of relevant issues that may arise as a consequence of our new technology and categorize them into three classes. We also introduce four normative ethical approaches that are used as a framework for decision-making. Despite the focus on vaccination strategies, our goal is to improve the discussions surrounding public concern and trust over artificial intelligence and demonstrate that artificial intelligence practitioners are addressing these concerns.

Vaccinating a Population is a Programming Problem

It is important to understand how best to apply a limited number of vaccines to a population such that the spread of a disease, like SARS-CoV-2, is minimized. Although intuition provides a number of mitigation strategies that may be effective, they remain largely untested. A system was developed to test a given disease mitigation strategy. It is designed to work with a graph representing a real social network. A Genetic Programming system was used to discover novel mitigation strategies that are easily interpretable by a public health decision maker. Effective strategies were developed by the GP system. The strategies are easily explainable and intuitive. Novel mitigation strategies were compared to simple baseline strategies with varying success using a number of different metrics. Many of these strategies proved effective in general, however the topology of the graph influences the effectiveness of a strategy. The system has been made publicly available and the authors call on the research community to contribute their own mitigation strategies and measure their efficacy.

FRCS General Surgery section-2 examination preparation during COVID-19 pandemic: an innovative and sustainable model

Background: The Joint Committee on Intercollegiate Examinations (JCIE- domestic) is responsible for the supervision of standards, policies, regulations and professional conduct of the UK/Ireland Specialty Fellowship Examinations. The Joint Surgical Colleges’ Fellowship Examination (JSCFE- International) is organised by the JSCFE Committee in five specialities, and one of them is General Surgery. The syllabus for the examination is extensive and needs rigorous preparation. The Specialty Trainees (ST) get supervised structured training and regular assessments, and hence their pass rate is not only comparatively higher, but they are better prepared for the challenge. However, trainee surgeons who are outside the UK training programmes find the examination difficult. The COVID-19 pandemic has impacted surgical training and education by limiting access to conventional teaching methods and available resources. We have been running a teaching and formative assessment platform since May 2017. This teaching resource has helped several trainees in passing the examination and has proven to be a valuable learning resource in the pandemic. Materials and Methods: We provided examination support, guidance and supervision by running Skype/ Microsoft Teams sessions and weekend courses. We emphasised five critical steps in all our sessions and used our course website- WWW.PHOENIXFRCSCOURSE.COM for material 1- Using Landing Sentences to start at the MRCS level 2- 0- 60 mph concept - a safe but quick pace to move from the MRCS zone onto the FRCS zone 3- The MISTER-model of simulation and learning 4- Maintaining pace and grace under pressure 5- Interleaving- revising, rehearsing and consolidating difficult topics The sessions included model scenarios, table viva, academic reading, virtual clinics and peer to peer learning (Examiners’ Drills). The faculty were recent examination graduates and had attended such sessions before their exam success. We followed the JCIE marking descriptors for formative assessment and timely feedback. Results: The first such course was organised in May 2017 and since then (over 40 months) a total of 100 attendees: 90 candidates (domestic FRCS and International FRCS) and 10 observers went through our sessions and workshops. Some 50 virtual sessions and 8 courses (16 days of simulation workshops) have been held so far. 66 (15 CCT and 51 non-CCT) candidates took the examination and 54 passed (82%). Sum 23 candidates have either deferred their examination dates or have been delayed because of the COVID-19 pandemic and are being regularly supported. Conclusions: Simulation-based virtual teaching supplemented with weekend inhouse courses has the potential to improve FRCS Section-2 examination preparation and the success rate during COVID-19 pandemic.