Classical and Quantum Equations of Motion for a BTZ Black String in AdS Space

We investigate gravitational collapse of a $(3+1)$-dimensional BTZ black string in AdS space in the context of both classical and quantum mechanics. This is done by first deriving the conserved mass per unit length of the cylindrically symmetric domain wall, which is taken as the classical Hamiltonian of the black string. In the quantum mechanical context, we take primary interest in the behavior of the collapse near the horizon and near the origin (classical singularity) from the point of view of an infalling observer. In the absence of radiation, quantum effects near the horizon do not change the classical conclusions for an infalling observer, meaning that the horizon is not an obstacle for him/her. The most interesting quantum mechanical effect comes in when investigating near the origin. First, quantum effects are able to remove the classical singularity at the origin, since the wave function is non-singular at the origin. Second, the Schr\"odinger equation describing the behavior near the origin displays non-local effects, which depend on the energy density of the domain wall. This is manifest in that derivatives of the wavefunction at one point are related to the value of the wavefunction at some other distant point.Comment: 9 pages, 1 figure. Minor Clarification and corrections. Accepted for Publication in JHE

Preclinical Development of an In Vivo BCG Challenge Model for Testing Candidate TB Vaccine Efficacy

There is an urgent need for an immunological correlate of protection against tuberculosis (TB) with which to evaluate candidate TB vaccines in clinical trials. Development of a human challenge model of Mycobacterium tuberculosis (M.tb) could facilitate the detection of such correlate(s). Here we propose a novel in vivo Bacille Calmette-Guérin (BCG) challenge model using BCG immunization as a surrogate for M.tb infection. Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin. Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge. Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection

Quantum Gravity in 2+1 Dimensions: The Case of a Closed Universe

In three spacetime dimensions, general relativity drastically simplifies, becoming a ``topological'' theory with no propagating local degrees of freedom. Nevertheless, many of the difficult conceptual problems of quantizing gravity are still present. In this review, I summarize the rather large body of work that has gone towards quantizing (2+1)-dimensional vacuum gravity in the setting of a spatially closed universe.Comment: 61 pages, draft of review for Living Reviews; comments, criticisms, additions, missing references welcome; v2: minor changes, added reference

Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection

The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF50) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines

Reactogenicity, immunogenicity and breakthrough infections following heterologous or fractional second dose COVID-19 vaccination in adolescents (Com-COV3): A Randomised Controlled Trial.

BACKGROUND: This was the first study to investigate the reactogenicity and immunogenicity of heterologous or fractional second dose COVID-19 vaccine regimens in adolescents. METHODS: A phase II, single-blind, multi-centre, randomised-controlled trial recruited across seven UK sites from September to November 2021, with follow-up visits to August 2022. Healthy 12-to-16 years olds were randomised (1:1:1) to either 30µg BNT162b2 (BNT-30), 10µg BNT162b2 (BNT-10), or NVX-CoV2373 (NVX), eight weeks after a first 30µg dose of BNT162b2. The primary outcome was solicited systemic reactions in the week following vaccination. Secondary outcomes included immunogenicity and safety. 'Breakthrough infection' analyses were exploratory. FINDINGS: 148 participants were recruited (median age 14 years old, 62% female, 26% anti-nucleocapsid IgG seropositive pre-second dose); 132 participants received a second dose. Reactions were mostly mild-to-moderate, with lower rates in BNT-10 recipients. No vaccine-related serious adverse events occurred. Compared to BNT-30, at 28 days post-second dose anti-spike antibody responses were similar for NVX [adjusted geometric mean ratio (aGMR) 1.09 95% confidence interval (CI): 0.84, 1.42] and lower for BNT-10 [aGMR 0.78 (95% CI: 0.61, 0.99)]. For Omicron BA.1 and BA.2, the neutralising antibody titres for BNT-30 at day 28 were similar for BNT-10 [aGMR 1.0 (95% CI: 0.65, 1.54) and 1.02 (95% CI: 0.71, 1.48), respectively], but higher for NVX [aGMR 1.7 (95% CI: 1.07, 2.69) and 1.43 (95% CI: 0.96, 2.12), respectively]. Compared to BNT-30, cellular immune responses were greatest for NVX [aGMR 1.73 (95% CI: 0.94, 3.18)], and lowest for BNT-10 [aGMR 0.65 (95% CI: 0.37, 1.15)] at 14 days post-second dose. Cellular responses were similar across the study arms by day 236 post-second dose. Amongst SARS-CoV-2 infection naïve participants, NVX participants had an 89% reduction in risk of self-reported 'breakthrough infection' compared to BNT-30 [adjusted hazard ratio (aHR) 0.11 (95% CI: 0.01, 0.86)] up until day 132 after second dose. BNT-10 recipients were more likely to have a 'breakthrough infection' compared to BNT-30 [aHR 2.14 (95% CI: 1.02, 4.51)] up to day 132 and day 236 post-second dose. Antibody responses at 132 and 236 days after second dose were similar for all vaccine schedules. INTERPRETATION: Heterologous and fractional dose COVID-19 vaccine schedules in adolescents are safe, well-tolerated and immunogenic. The enhanced performance of the heterologous schedule using NVX-CoV2373 against the Omicron SARS-CoV-2 variant suggests this mRNA prime and protein-subunit boost schedule may provide a greater breadth of protection than the licensed homologous schedule. FUNDING: National Institute for Health Research and Vaccine Task Force. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number registry: 12348322

Оценка качества образования на основе компетентностного подхода

В работе представлен практический опыт оценки качества образования в новом формате компетентностного подход

AZD1222/ChAdOx1 nCoV-19 vaccination induces a polyfunctional spike protein-specific Th1 response with a diverse TCR repertoire.

AZD1222 (ChAdOx1 nCoV-19), a replication-deficient simian adenovirus-vectored vaccine, has demonstrated safety, efficacy, and immunogenicity against coronavirus disease 2019 (COVID-19) in clinical trials and real-world studies. We characterized CD4+ and CD8+ T cell responses induced by AZD1222 vaccination in peripheral blood mononuclear cells (PBMCs) from 296 unique vaccine recipients aged 18 to 85 years who enrolled in the phase 2/3 COV002 trial. Total spike protein-specific CD4+ T cell helper type 1 (Th1) and CD8+ T cell responses were increased in AZD1222-vaccinated adults of all ages following two doses of AZD1222. CD4+ Th2 responses following AZD1222 vaccination were not detected. Furthermore, AZD1222-specific Th1 and CD8+ T cells both displayed a high degree of polyfunctionality in all adult age groups. T cell receptor (TCR) β sequences from vaccinated participants mapped against TCR sequences known to react to SARS-CoV-2 revealed substantial breadth and depth across the SARS-CoV-2 spike protein for both AZD1222-induced CD4+ and CD8+ T cell responses. Overall, AZD1222 vaccination induced a polyfunctional Th1-dominated T cell response, with broad CD4+ and CD8+ T cell coverage across the SARS-CoV-2 spike protein

Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection

The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF50) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines

Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002)

Background COVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between the first and second dose becomes longer. Conversely, countries with no supply constraints are considering administering a third dose. We assessed the persistence of immunogenicity after a single dose of ChAdOx1 nCoV-19 (AZD1222), immunity after an extended interval (44–45 weeks) between the first and second dose, and response to a third dose as a booster given 28–38 weeks after the second dose. Methods In this substudy, volunteers aged 18–55 years who were enrolled in the phase 1/2 (COV001) controlled trial in the UK and had received either a single dose or two doses of 5 × 1010 viral particles were invited back for vaccination. Here we report the reactogenicity and immunogenicity of a delayed second dose (44–45 weeks after first dose) or a third dose of the vaccine (28–38 weeks after second dose). Data from volunteers aged 18–55 years who were enrolled in either the phase 1/2 (COV001) or phase 2/3 (COV002), single-blinded, randomised controlled trials of ChAdOx1 nCoV-19 and who had previously received a single dose or two doses of 5 × 1010 viral particles are used for comparison purposes. COV001 is registered with ClinicalTrials.gov, NCT04324606, and ISRCTN, 15281137, and COV002 is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137, and both are continuing but not recruiting. Findings Between March 11 and 21, 2021, 90 participants were enrolled in the third-dose boost substudy, of whom 80 (89%) were assessable for reactogenicity, 75 (83%) were assessable for evaluation of antibodies, and 15 (17%) were assessable for T-cells responses. The two-dose cohort comprised 321 participants who had reactogenicity data (with prime-boost interval of 8–12 weeks: 267 [83%] of 321; 15–25 weeks: 24 [7%]; or 44–45 weeks: 30 [9%]) and 261 who had immunogenicity data (interval of 8–12 weeks: 115 [44%] of 261; 15–25 weeks: 116 [44%]; and 44–45 weeks: 30 [11%]). 480 participants from the single-dose cohort were assessable for immunogenicity up to 44–45 weeks after vaccination. Antibody titres after a single dose measured approximately 320 days after vaccination remained higher than the titres measured at baseline (geometric mean titre of 66·00 ELISA units [EUs; 95% CI 47·83–91·08] vs 1·75 EUs [1·60–1·93]). 32 participants received a late second dose of vaccine 44–45 weeks after the first dose, of whom 30 were included in immunogenicity and reactogenicity analyses. Antibody titres were higher 28 days after vaccination in those with a longer interval between first and second dose than for those with a short interval (median total IgG titre: 923 EUs [IQR 525–1764] with an 8–12 week interval; 1860 EUs [917–4934] with a 15–25 week interval; and 3738 EUs [1824–6625] with a 44–45 week interval). Among participants who received a third dose of vaccine, antibody titres (measured in 73 [81%] participants for whom samples were available) were significantly higher 28 days after a third dose (median total IgG titre: 3746 EUs [IQR 2047–6420]) than 28 days after a second dose (median 1792 EUs [IQR 899–4634]; Wilcoxon signed rank test p=0·0043). T-cell responses were also boosted after a third dose (median response increased from 200 spot forming units [SFUs] per million peripheral blood mononuclear cells [PBMCs; IQR 127–389] immediately before the third dose to 399 SFUs per milion PBMCs [314–662] by day 28 after the third dose; Wilcoxon signed rank test p=0·012). Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose. Interpretation An extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titres. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlates with high efficacy after second dose and boosts T-cell responses. Funding UK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, AstraZeneca, and Wellcome