Comprehensive analysis of the efficacy and safety of CAR T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia: a systematic review and meta-analysis.

BACKGROUND: Relapse/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL) represents paediatric cancer with a challenging prognosis. CAR T-cell treatment, considered an advanced treatment, remains controversial due to high relapse rates and adverse events. This study assessed the efficacy and safety of CAR T-cell therapy for r/r B-ALL. METHODS: The literature search was performed on four databases. Efficacy parameters included minimal residual disease negative complete remission (MRD-CR) and relapse rate (RR). Safety parameters constituted cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). RESULTS: Anti-CD22 showed superior efficacy with the highest MRD-CR event rate and lowest RR, compared to anti-CD19. Combining CAR T-cell therapy with haploidentical stem cell transplantation improved RR. Safety-wise, bispecific anti-CD19/22 had the lowest CRS rate, and anti-CD22 showed the fewest ICANS. Analysis of the costimulatory receptors showed that adding CD28ζ to anti-CD19 CAR T-cell demonstrated superior efficacy in reducing relapses with favorable safety profiles. CONCLUSION: Choosing a more efficacious and safer CAR T-cell treatment is crucial for improving overall survival in acute leukaemia. Beyond the promising anti-CD22 CAR T-cell, exploring costimulatory domains and new CD targets could enhance treatment effectiveness for r/r B-ALL.

Generation of SARS-CoV-2 escape mutations by monoclonal antibody therapy.

COVID-19 patients at risk of severe disease may be treated with neutralising monoclonal antibodies (mAbs). To minimise virus escape from neutralisation these are administered as combinations e.g. casirivimab+imdevimab or, for antibodies targeting relatively conserved regions, individually e.g. sotrovimab. Unprecedented genomic surveillance of SARS-CoV-2 in the UK has enabled a genome-first approach to detect emerging drug resistance in Delta and Omicron cases treated with casirivimab+imdevimab and sotrovimab respectively. Mutations occur within the antibody epitopes and for casirivimab+imdevimab multiple mutations are present on contiguous raw reads, simultaneously affecting both components. Using surface plasmon resonance and pseudoviral neutralisation assays we demonstrate these mutations reduce or completely abrogate antibody affinity and neutralising activity, suggesting they are driven by immune evasion. In addition, we show that some mutations also reduce the neutralising activity of vaccine-induced serum.

Evolution of long-term vaccine-induced and hybrid immunity in healthcare workers after different COVID-19 vaccine regimens.

BACKGROUND: Both infection and vaccination, alone or in combination, generate antibody and T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the maintenance of such responses-and hence protection from disease-requires careful characterization. In a large prospective study of UK healthcare workers (HCWs) (Protective Immunity from T Cells in Healthcare Workers [PITCH], within the larger SARS-CoV-2 Immunity and Reinfection Evaluation [SIREN] study), we previously observed that prior infection strongly affected subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. METHODS: Here, we report longer follow-up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. FINDINGS: We make three observations: first, the dynamics of humoral and cellular responses differ; binding and neutralizing antibodies declined, whereas T and memory B cell responses were maintained after the second vaccine dose. Second, vaccine boosting restored immunoglobulin (Ig) G levels; broadened neutralizing activity against variants of concern, including Omicron BA.1, BA.2, and BA.5; and boosted T cell responses above the 6-month level after dose 2. Third, prior infection maintained its impact driving larger and broader T cell responses compared with never-infected people, a feature maintained until 6 months after the third dose. CONCLUSIONS: Broadly cross-reactive T cell responses are well maintained over time-especially in those with combined vaccine and infection-induced immunity ("hybrid" immunity)-and may contribute to continued protection against severe disease. FUNDING: Department for Health and Social Care, Medical Research Council.

Porous Cellulose Thin Films as Sustainable and Effective Antimicrobial Surface Coatings.

In the present work, we developed an effective antimicrobial surface film based on sustainable microfibrillated cellulose. The resulting porous cellulose thin film is barely noticeable to human eyes due to its submicrometer thickness, of which the surface coverage, porosity, and microstructure can be modulated by the formulations and the coating process. Using goniometers and a quartz crystal microbalance, we observed a threefold reduction in water contact angles and accelerated water evaporation kinetics on the cellulose film (more than 50% faster than that on a flat glass surface). The porous cellulose film exhibits a rapid inactivation effect against SARS-CoV-2 in 5 min, following deposition of virus-loaded droplets, and an exceptional ability to reduce contact transfer of liquid, e.g., respiratory droplets, to surfaces such as an artificial skin by 90% less than that from a planar glass substrate. It also shows excellent antimicrobial performance in inhibiting the growth of both Gram-negative and Gram-positive bacteria (Escherichia coli and Staphylococcus epidermidis) due to the intrinsic porosity and hydrophilicity. Additionally, the cellulose film shows nearly 100% resistance to scraping in dry conditions due to its strong affinity to the supporting substrate but with good removability once wetted with water, suggesting its practical suitability for daily use. Importantly, the coating can be formed on solid substrates readily by spraying, which requires solely a simple formulation of a plant-based cellulose material with no chemical additives, rendering it a scalable, affordable, and green solution as antimicrobial surface coating. Implementing such cellulose films could thus play a significant role in controlling future pan- and epidemics, particularly during the initial phase when suitable medical intervention needs to be developed and deployed.

A delicate balance between antibody evasion and ACE2 affinity for Omicron BA.2.75.

Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused successive global waves of infection. These variants, with multiple mutations in the spike protein, are thought to facilitate escape from natural and vaccine-induced immunity and often increase in affinity for ACE2. The latest variant to cause concern is BA.2.75, identified in India where it is now the dominant strain, with evidence of wider dissemination. BA.2.75 is derived from BA.2 and contains four additional mutations in the receptor-binding domain (RBD). Here, we perform an antigenic and biophysical characterization of BA.2.75, revealing an interesting balance between humoral evasion and ACE2 receptor affinity. ACE2 affinity for BA.2.75 is increased 9-fold compared with BA.2; there is also evidence of escape of BA.2.75 from immune serum, particularly that induced by Delta infection, which may explain the rapid spread in India, where where there is a high background of Delta infection. ACE2 affinity appears to be prioritized over greater escape.

Genotypic and phenotypic profiles of EYS gene-related retinitis pigmentosa: a retrospective study.

Retinitis pigmentosa (RP) affects 1:5000 individuals worldwide. Interestingly, variations in 271 RP-related genes are indicated to vary among populations. We aimed to evaluate the genetic prevalence and phenotypic profiles of Thai patients with RP. The clinical and whole exome sequencing data of 125 patients suggestive of inherited retinal diseases (IRD), particularly non-syndromic RP, were assessed. We found a total of 258 variants (63% of which remained unavailable in the ClinVar database) in 91 IRD-associated genes. Among the detected genes, the eyes shut homolog (EYS) gene showed the highest prevalence. We also provide insights into the genotypic, baseline, and follow-up clinical presentations of seven patients with disease-causing EYS variations. This study could provide comprehension of the prevalence of RP-related genes involved in the Asian population. It might also provide information to establish advanced and personalised therapy for RP in the Thai population.

Potent cross-reactive antibodies following Omicron breakthrough in vaccinees.

Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focused in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains, and many show broad reactivity with variants of concern.

Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum.

The Omicron lineage of SARS-CoV-2, which was first described in November 2021, spread rapidly to become globally dominant and has split into a number of sublineages. BA.1 dominated the initial wave but has been replaced by BA.2 in many countries. Recent sequencing from South Africa's Gauteng region uncovered two new sublineages, BA.4 and BA.5, which are taking over locally, driving a new wave. BA.4 and BA.5 contain identical spike sequences, and although closely related to BA.2, they contain further mutations in the receptor-binding domain of their spikes. Here, we study the neutralization of BA.4/5 using a range of vaccine and naturally immune serum and panels of monoclonal antibodies. BA.4/5 shows reduced neutralization by the serum from individuals vaccinated with triple doses of AstraZeneca or Pfizer vaccine compared with BA.1 and BA.2. Furthermore, using the serum from BA.1 vaccine breakthrough infections, there are, likewise, significant reductions in the neutralization of BA.4/5, raising the possibility of repeat Omicron infections.

SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses.

On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses.

The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants.

Alpha-B.1.1.7, Beta-B.1.351, Gamma-P.1, and Delta-B.1.617.2 variants of SARS-CoV-2 express multiple mutations in the spike protein (S). These may alter the antigenic structure of S, causing escape from natural or vaccine-induced immunity. Beta is particularly difficult to neutralize using serum induced by early pandemic SARS-CoV-2 strains and is most antigenically separated from Delta. To understand this, we generated 674 mAbs from Beta-infected individuals and performed a detailed structure-function analysis of the 27 most potent mAbs: one binding the spike N-terminal domain (NTD), the rest the receptor-binding domain (RBD). Two of these RBD-binding mAbs recognize a neutralizing epitope conserved between SARS-CoV-1 and -2, while 18 target mutated residues in Beta: K417N, E484K, and N501Y. There is a major response to N501Y, including a public IgVH4-39 sequence, with E484K and K417N also targeted. Recognition of these key residues underscores why serum from Beta cases poorly neutralizes early pandemic and Delta viruses.

Rare Co-Occurrence of Visual Snow in a Female Carrier With RPGRORF15-Associated Retinal Disorder.

X-linked retinitis pigmentosa (XLRP), a rare form of retinitis pigmentosa (RP), is predominantly caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. Affected males often present with severe phenotypes and early disease onset. In contrast, female carriers are usually asymptomatic or show stationary phenotypes. Herein, we reported an 8-year-old female carrier, a daughter of a confirmed RP father with RPGR mutation, with an early onset of progressive cone-rod pattern retinal dystrophy. Additionally, the carrier experienced visual snow-like symptom as long as she recalled. Ophthalmological examination showed the reduction of visual acuity and attenuation of photoreceptor functions since the age of 5 years. Further analysis revealed a heterozygous pathogenic variant of the RPGR gene and a random X-inactivation pattern. Although she harboured an identical RPGR variant as the father, there were phenotypic intrafamilial variations. The information on the variety of genotypic and phenotypic presentations in XLRP carriers is essential for further diagnosis, management, and monitoring of these cases, including the design of future gene therapy trials.

Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone progressive change, with variants conferring advantage rapidly becoming dominant lineages, e.g., B.1.617. With apparent increased transmissibility, variant B.1.617.2 has contributed to the current wave of infection ravaging the Indian subcontinent and has been designated a variant of concern in the United Kingdom. Here we study the ability of monoclonal antibodies and convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2, complement this with structural analyses of Fab/receptor binding domain (RBD) complexes, and map the antigenic space of current variants. Neutralization of both viruses is reduced compared with ancestral Wuhan-related strains, but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2, suggesting that individuals infected previously by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insights for immunization policy with future variant vaccines in non-immune populations.

Autoantibody profiles and clinical association in Thai patients with autoimmune retinopathy.

Autoimmune retinopathy (AIR) is a rare immune-mediated inflammation of the retina. The autoantibodies against retinal proteins and glycolytic enzymes were reported to be involved in the pathogenesis. This retrospective cohort study assessed the antiretinal autoantibody profiles and their association with clinical outcomes of AIR patients in Thailand. We included 44 patients, 75% were females, with the overall median age of onset of 48 (17-74, IQR 40-55.5) years. Common clinical presentations were nyctalopia (65.9%), blurred vision (52.3%), constricted visual field (43.2%), and nonrecordable electroretinography (65.9%). Underlying malignancy and autoimmune diseases were found in 2 and 12 female patients, respectively. We found 41 autoantibodies, with anti-α-enolase (65.9%) showing the highest prevalence, followed by anti-CAII (43.2%), anti-aldolase (40.9%), and anti-GAPDH (36.4%). Anti-aldolase was associated with male gender (P = 0.012, OR 7.11, 95% CI 1.54-32.91). Anti-CAII showed significant association with age of onset (P = 0.025, 95% CI - 17.28 to - 1.24), while anti-α-enolase (P = 0.002, OR 4.37, 95% CI 1.83-10.37) and anti-GAPDH (P = 0.001, OR 1.87, 95% CI 1.32-2.64) were significantly associated with nonrecordable electroretinography. Association between the antibody profiles and clinical outcomes may be used to direct and adjust the treatment plans and provide insights in the pathogenesis of AIR.

Antibody evasion by the P.1 strain of SARS-CoV-2.

Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations, including P.1 from Brazil, B.1.351 from South Africa, and B.1.1.7 from the UK (12, 10, and 9 changes in the spike, respectively). All have mutations in the ACE2 binding site, with P.1 and B.1.351 having a virtually identical triplet (E484K, K417N/T, and N501Y), which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine-induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain (RBD) impact neutralization. Monoclonal antibody (mAb) 222 neutralizes all three variants despite interacting with two of the ACE2-binding site mutations. We explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.

Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera.

SARS-CoV-2 has caused over 2 million deaths in little over a year. Vaccines are being deployed at scale, aiming to generate responses against the virus spike. The scale of the pandemic and error-prone virus replication is leading to the appearance of mutant viruses and potentially escape from antibody responses. Variant B.1.1.7, now dominant in the UK, with increased transmission, harbors 9 amino acid changes in the spike, including N501Y in the ACE2 interacting surface. We examine the ability of B.1.1.7 to evade antibody responses elicited by natural SARS-CoV-2 infection or vaccination. We map the impact of N501Y by structure/function analysis of a large panel of well-characterized monoclonal antibodies. B.1.1.7 is harder to neutralize than parental virus, compromising neutralization by some members of a major class of public antibodies through light-chain contacts with residue 501. However, widespread escape from monoclonal antibodies or antibody responses generated by natural infection or vaccination was not observed.

Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera.

The race to produce vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began when the first sequence was published, and this forms the basis for vaccines currently deployed globally. Independent lineages of SARS-CoV-2 have recently been reported: UK, B.1.1.7; South Africa, B.1.351; and Brazil, P.1. These variants have multiple changes in the immunodominant spike protein that facilitates viral cell entry via the angiotensin-converting enzyme-2 (ACE2) receptor. Mutations in the receptor recognition site on the spike are of great concern for their potential for immune escape. Here, we describe a structure-function analysis of B.1.351 using a large cohort of convalescent and vaccinee serum samples. The receptor-binding domain mutations provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization largely driven by E484K, although K417N and N501Y act together against some important antibody classes. In a number of cases, it would appear that convalescent and some vaccine serum offers limited protection against this variant.

Intravitreal autologous mesenchymal stem cell transplantation: a non-randomized phase I clinical trial in patients with retinitis pigmentosa.

BACKGROUND: Retinitis pigmentosa (RP) is a progressive inherited retinal disease with great interest for finding effective treatment modalities. Stem cell-based therapy is one of the promising candidates. We aimed to investigate the safety, feasibility, and short-term efficacy of intravitreal injection of bone marrow-derived mesenchymal stem cells (BM-MSCs) in participants with advanced stage RP. METHODS: This non-randomized phase I clinical trial enrolled 14 participants, categorized into three groups based on a single dose intravitreal BM-MSC injection of 1 × 106, 5 × 106, or 1 × 107 cells. We evaluated signs of inflammation and other adverse events (AEs). We also assessed the best corrected visual acuity (BCVA), visual field (VF), central subfield thickness (CST), and subjective experiences. RESULTS: During the 12-month period, we noticed several mild and transient AEs. Interestingly, we found statistically significant improvements in the BCVA compared to baseline, although they returned to the baseline at 12 months. The VF and CST were stable, indicating no remarkable disease progression. We followed 12 participants beyond the study period, ranging from 1.5 to 7 years, and observed one severe but manageable AE at year 3. CONCLUSION: Intravitreal injection of BM-MSCs appears to be safe and potentially effective. All adverse events during the 12-month period required observation without any intervention. For the long-term follow-up, only one participant needed surgical treatment for a serious adverse event and the vision was restored. An enrollment of larger number of participants with less advanced RP and long-term follow-up is required to evaluate the safety and efficacy of this intervention. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01531348 . Registered on February 10, 2012.

Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses.

On the 24 th November 2021 the sequence of a new SARS CoV-2 viral isolate spreading rapidly in Southern Africa was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titres of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic as well as Alpha, Beta, Gamma, Delta are substantially reduced or fail to neutralize. Titres against Omicron are boosted by third vaccine doses and are high in cases both vaccinated and infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of a large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses, combining mutations conferring tight binding to ACE2 to unleash evolution driven by immune escape, leading to a large number of mutations in the ACE2 binding site which rebalance receptor affinity to that of early pandemic viruses.

Molecular and clinical characterization of Thai patients with achromatopsia: identification of three novel disease-associated variants in the CNGA3 and CNGB3 genes.

PURPOSE: Achromatopsia (ACHM) is an autosomal recessive cone disorder characterized by pendular nystagmus, photophobia, reduced visual acuity, and partial or total absence of color vision. Mutations in six genes (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6) have been reported in ACHM. There is no information on these disease-associated genes in Thai population. This study aimed to investigate the molecular and clinical characteristics in Thai patients with ACHM. METHODS: Seven unrelated Thai patients with ACHM were recruited. Detailed ophthalmologic examination was performed. Polymerase chain reaction (PCR)-coupled single-strand conformation polymorphism (SSCP) screening followed by Sanger sequencing was used to identify sequence variants in all exons and splice junctions of three genes (CNGA3, CNGB3, and GNAT2). The pathogenicity of the detected variants was interpreted. Segregation analysis was performed to determine variant sharing in available family members. RESULTS: Four patients displayed different SSCP migration patterns. Sequence analysis revealed a reported pathogenic and a novel disease-associated variant in the CNGA3 gene. For the CNGB3 gene, we found two novel disease-associated variants and a reported variant of uncertain significance (VUS). Segregation analysis confirmed that the variants identified in each patient were present in the heterozygous state in their corresponding family members, which was consistent with an autosomal recessive mode of inheritance. CONCLUSIONS: This study demonstrated the first molecular and clinical characterization of ACHM in Thai patients. The identification of disease-associated genes in a specific population leads to a personalized gene therapy benefiting those affected patients.