Journal: Nat Med

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Abstract

Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection.

Patone M, Handunnetthi L, Saatci D, Pan J, ... Robertson C, Hippisley-Cox J
Emerging reports of rare neurological complications associated with COVID-19 infection and vaccinations are leading to regulatory, clinical and public health concerns. We undertook a self-controlled case series study to investigate hospital admissions from neurological complications in the 28 days after a first dose of ChAdOx1nCoV-19 (n = 20,417,752) or BNT162b2 (n = 12,134,782), and after a SARS-CoV-2-positive test (n = 2,005,280). There was an increased risk of Guillain-Barré syndrome (incidence rate ratio (IRR), 2.90; 95% confidence interval (CI): 2.15-3.92 at 15-21 days after vaccination) and Bell\'s palsy (IRR, 1.29; 95% CI: 1.08-1.56 at 15-21 days) with ChAdOx1nCoV-19. There was an increased risk of hemorrhagic stroke (IRR, 1.38; 95% CI: 1.12-1.71 at 15-21 days) with BNT162b2. An independent Scottish cohort provided further support for the association between ChAdOx1nCoV and Guillain-Barré syndrome (IRR, 2.32; 95% CI: 1.08-5.02 at 1-28 days). There was a substantially higher risk of all neurological outcomes in the 28 days after a positive SARS-CoV-2 test including Guillain-Barré syndrome (IRR, 5.25; 95% CI: 3.00-9.18). Overall, we estimated 38 excess cases of Guillain-Barré syndrome per 10 million people receiving ChAdOx1nCoV-19 and 145 excess cases per 10 million people after a positive SARS-CoV-2 test. In summary, although we find an increased risk of neurological complications in those who received COVID-19 vaccines, the risk of these complications is greater following a positive SARS-CoV-2 test.

© 2021. The Author(s).

Nat Med: 24 Oct 2021; epub ahead of print
Patone M, Handunnetthi L, Saatci D, Pan J, ... Robertson C, Hippisley-Cox J
Nat Med: 24 Oct 2021; epub ahead of print | PMID: 34697502
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Abstract

IL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies.

Friedrich M, Pohin M, Jackson MA, Korsunsky I, ... Travis SP, Powrie FM
Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease.

© 2021. The Author(s).

Nat Med: 20 Oct 2021; epub ahead of print
Friedrich M, Pohin M, Jackson MA, Korsunsky I, ... Travis SP, Powrie FM
Nat Med: 20 Oct 2021; epub ahead of print | PMID: 34675383
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Abstract

Toxicity after AAV delivery of RNAi expression constructs into nonhuman primate brain.

Keiser MS, Ranum PT, Yrigollen CM, Carrell EM, ... Gonzalez-Alegre P, Davidson BL
RNA interference (RNAi) for spinocerebellar ataxia type 1 can prevent and reverse behavioral deficits and neuropathological readouts in mouse models, with safety and benefit lasting over many months. The RNAi trigger, expressed from adeno-associated virus vectors (AAV.miS1), also corrected misregulated microRNAs (miRNA) such as miR150. Subsequently, we showed that the delivery method was scalable, and that AAV.miS1 was safe in short-term pilot nonhuman primate (NHP) studies. To advance the technology to patients, investigational new drug (IND)-enabling studies in NHPs were initiated. After AAV.miS1 delivery to deep cerebellar nuclei, we unexpectedly observed cerebellar toxicity. Both small-RNA-seq and studies using AAVs devoid of miRNAs showed that this was not a result of saturation of the endogenous miRNA processing machinery. RNA-seq together with sequencing of the AAV product showed that, despite limited amounts of cross-packaged material, there was substantial inverted terminal repeat (ITR) promoter activity that correlated with neuropathologies. ITR promoter activity was reduced by altering the miS1 expression context. The surprising contrast between our rodent and NHP findings highlight the need for extended safety studies in multiple species when assessing new therapeutics for human application.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 17 Oct 2021; epub ahead of print
Keiser MS, Ranum PT, Yrigollen CM, Carrell EM, ... Gonzalez-Alegre P, Davidson BL
Nat Med: 17 Oct 2021; epub ahead of print | PMID: 34663988
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Abstract

Mutations and variants of ONECUT1 in diabetes.

Philippi A, Heller S, Costa IG, Senée V, ... Julier C, Kleger A
Genes involved in distinct diabetes types suggest shared disease mechanisms. Here we show that One Cut Homeobox 1 (ONECUT1) mutations cause monogenic recessive syndromic diabetes in two unrelated patients, characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia, and early-onset diabetes in heterozygous relatives. Heterozygous carriers of rare coding variants of ONECUT1 define a distinctive subgroup of diabetic patients with early-onset, nonautoimmune diabetes, who respond well to diabetes treatment. In addition, common regulatory ONECUT1 variants are associated with multifactorial type 2 diabetes. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. Loss of ONECUT1 altered transcription factor binding and enhancer activity and NKX2.2/NKX6.1 expression in pancreatic progenitor cells. Collectively, we demonstrate that ONECUT1 controls a transcriptional and epigenetic machinery regulating endocrine development, involved in a spectrum of diabetes, encompassing monogenic (recessive and dominant) as well as multifactorial inheritance. Our findings highlight the broad contribution of ONECUT1 in diabetes pathogenesis, marking an important step toward precision diabetes medicine.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 17 Oct 2021; epub ahead of print
Philippi A, Heller S, Costa IG, Senée V, ... Julier C, Kleger A
Nat Med: 17 Oct 2021; epub ahead of print | PMID: 34663987
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Abstract

Distinction of lymphoid and myeloid clonal hematopoiesis.

Niroula A, Sekar A, Murakami MA, Trinder M, ... Natarajan P, Ebert BL
Clonal hematopoiesis (CH) results from somatic genomic alterations that drive clonal expansion of blood cells. Somatic gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of indeterminate potential (CHIP), have been associated with myeloid malignancies, while mosaic chromosomal alterations (mCAs) have been associated with lymphoid malignancies. Here, we analyzed CHIP in 55,383 individuals and autosomal mCAs in 420,969 individuals with no history of hematologic malignancies in the UK Biobank and Mass General Brigham Biobank. We distinguished myeloid and lymphoid somatic gene mutations, as well as myeloid and lymphoid mCAs, and found both to be associated with risk of lineage-specific hematologic malignancies. Further, we performed an integrated analysis of somatic alterations with peripheral blood count parameters to stratify the risk of incident myeloid and lymphoid malignancies. These genetic alterations can be readily detected in clinical sequencing panels and used with blood count parameters to identify individuals at high risk of developing hematologic malignancies.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 17 Oct 2021; epub ahead of print
Niroula A, Sekar A, Murakami MA, Trinder M, ... Natarajan P, Ebert BL
Nat Med: 17 Oct 2021; epub ahead of print | PMID: 34663986
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Abstract

Effect of Delta variant on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK.

Pouwels KB, Pritchard E, Matthews PC, Stoesser N, ... Diamond I, Walker AS
The effectiveness of the BNT162b2 and ChAdOx1 vaccines against new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections requires continuous re-evaluation, given the increasingly dominant B.1.617.2 (Delta) variant. In this study, we investigated the effectiveness of these vaccines in a large, community-based survey of randomly selected households across the United Kingdom. We found that the effectiveness of BNT162b2 and ChAdOx1 against infections (new polymerase chain reaction (PCR)-positive cases) with symptoms or high viral burden is reduced with the B.1.617.2 variant (absolute difference of 10-13% for BNT162b2 and 16% for ChAdOx1) compared to the B.1.1.7 (Alpha) variant. The effectiveness of two doses remains at least as great as protection afforded by prior natural infection. The dynamics of immunity after second doses differed significantly between BNT162b2 and ChAdOx1, with greater initial effectiveness against new PCR-positive cases but faster declines in protection against high viral burden and symptomatic infection with BNT162b2. There was no evidence that effectiveness varied by dosing interval, but protection was higher in vaccinated individuals after a prior infection and in younger adults. With B.1.617.2, infections occurring after two vaccinations had similar peak viral burden as those in unvaccinated individuals. SARS-CoV-2 vaccination still reduces new infections, but effectiveness and attenuation of peak viral burden are reduced with B.1.617.2.

© 2021. The Author(s).

Nat Med: 13 Oct 2021; epub ahead of print
Pouwels KB, Pritchard E, Matthews PC, Stoesser N, ... Diamond I, Walker AS
Nat Med: 13 Oct 2021; epub ahead of print | PMID: 34650248
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Abstract

Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial.

Yuen MF, Heo J, Jang JW, Yoon JH, ... Bennett CF, Kwoh TJ
Chronic infection with hepatitis B virus (HBV) leads to an increased risk of death from cirrhosis and hepatocellular carcinoma. Functional cure rates are low with current treatment options (nucleos(t)ide analogs (NAs) and pegylated interferons). Bepirovirsen is an antisense oligonucleotide targeting all HBV messenger RNAs; in cell culture and animal models, bepirovirsen leads to reductions in HBV-derived RNAs, HBV DNA and viral proteins. This phase 2 double-blinded, randomized, placebo-controlled trial is the first evaluation of the safety and activity of an antisense oligonucleotide targeting HBV RNA in both treatment-naïve and virally suppressed individuals with chronic HBV infection. The primary objective was to assess the safety and tolerability of bepirovirsen in individuals with chronic hepatitis B (CHB) (NCT02981602). The secondary objective was to assess antiviral activity, including the change from baseline to day 29 in serum hepatitis B surface antigen (HBsAg) concentration. Participants with CHB infection ≥6 months and serum HBsAg ≥50 IU ml-1 were enrolled from seven centers across Hong Kong and the Republic of Korea and randomized (3:1 within each dose cohort) to receive bepirovirsen or placebo via subcutaneous injection twice weekly during weeks 1 and 2 (days 1, 4, 8 and 11) and once weekly during weeks 3 and 4 (days 15 and 22). Participants were then followed for 26 weeks. Twenty-four participants were treatment-naïve and seven were receiving stable NA therapy. Treatment-emergent adverse events were mostly mild/moderate (most commonly injection site reactions). Eleven (61.1%) and three (50.0%) treatment-naïve participants experienced one or more treatment-emergent adverse event in the bepirovirsen and placebo groups, respectively. In participants receiving NA therapy, the corresponding numbers were three (60.0%) and one (50.0%). Transient, self-resolving alanine aminotransferase flares (≥2× upper limit of normal) were observed in eight treatment-naïve participants and three participants on stable NA regimens in the bepirovirsen treatment arms. HBsAg reductions were observed and were significant versus placebo for treatment-naïve participants receiving bepirovirsen 300 mg (P = 0.001), but not for the bepirovirsen 150 mg group (P = 0.245) or participants receiving stable NA therapy (P = 0.762). Two participants in each of the 300 mg dose groups achieved HBsAg levels below the lower limit of quantitation by day 29 (n = 3) or day 36 (n = 1). Bepirovirsen had a favorable safety profile. These preliminary observations warrant further investigation of the safety and activity of bepirovirsen in a larger CHB patient population.

© 2021. The Author(s).

Nat Med: 11 Oct 2021; epub ahead of print
Yuen MF, Heo J, Jang JW, Yoon JH, ... Bennett CF, Kwoh TJ
Nat Med: 11 Oct 2021; epub ahead of print | PMID: 34642494
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Abstract

Anemia prevalence in women of reproductive age in low- and middle-income countries between 2000 and 2018.

Kinyoki D, Osgood-Zimmerman AE, Bhattacharjee NV, Local Burden of Disease Anaemia Collaborators, Kassebaum NJ, Hay SI
Anemia is a globally widespread condition in women and is associated with reduced economic productivity and increased mortality worldwide. Here we map annual 2000-2018 geospatial estimates of anemia prevalence in women of reproductive age (15-49 years) across 82 low- and middle-income countries (LMICs), stratify anemia by severity and aggregate results to policy-relevant administrative and national levels. Additionally, we provide subnational disparity analyses to provide a comprehensive overview of anemia prevalence inequalities within these countries and predict progress toward the World Health Organization\'s Global Nutrition Target (WHO GNT) to reduce anemia by half by 2030. Our results demonstrate widespread moderate improvements in overall anemia prevalence but identify only three LMICs with a high probability of achieving the WHO GNT by 2030 at a national scale, and no LMIC is expected to achieve the target in all their subnational administrative units. Our maps show where large within-country disparities occur, as well as areas likely to fall short of the WHO GNT, offering precision public health tools so that adequate resource allocation and subsequent interventions can be targeted to the most vulnerable populations.

© 2021. The Author(s).

Nat Med: 11 Oct 2021; epub ahead of print
Kinyoki D, Osgood-Zimmerman AE, Bhattacharjee NV, Local Burden of Disease Anaemia Collaborators, Kassebaum NJ, Hay SI
Nat Med: 11 Oct 2021; epub ahead of print | PMID: 34642490
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Abstract

CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial.

Cordoba S, Onuoha S, Thomas S, Pignataro DS, ... Pule M, Amrolia PJ
Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3-5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.

© 2021. The Author(s).

Nat Med: 11 Oct 2021; epub ahead of print
Cordoba S, Onuoha S, Thomas S, Pignataro DS, ... Pule M, Amrolia PJ
Nat Med: 11 Oct 2021; epub ahead of print | PMID: 34642489
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Abstract

Individualized therapy trials: navigating patient care, research goals and ethics.

Kane PB, Bittlinger M, Kimmelman J
\'Individualized therapy\' trials (sometimes called n-of-1 trials) use patients as their own controls to evaluate treatments. Here we divide such trials into three categories: multi-crossover trials aimed at individual patient management, multi-crossover trial series and pre-post trials. These trials all customize interventions for patients; however, the latter two categories also aim to inform medical practice and thus embody tensions between the goals of care and research that are typical of other types of clinical trials. In this Perspective, we discuss four domains where such tensions play out-clinical equipoise, informed consent, reporting and funding, and we provide recommendations for addressing each.

© 2021. Springer Nature America, Inc.

Nat Med: 11 Oct 2021; epub ahead of print
Kane PB, Bittlinger M, Kimmelman J
Nat Med: 11 Oct 2021; epub ahead of print | PMID: 34642487
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Abstract

ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials.

Calle RA, Amin NB, Carvajal-Gonzalez S, Ross TT, ... Pfefferkorn JA, Esler WP
Alterations in lipid metabolism might contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, no pharmacological agents are currently approved in the United States or the European Union for the treatment of NAFLD. Two parallel phase 2a studies investigated the effects of liver-directed ACC1/2 inhibition in adults with NAFLD. The first study ( NCT03248882 ) examined the effects of monotherapy with a novel ACC1/2 inhibitor, PF-05221304 (2, 10, 25 and 50 mg once daily (QD)), versus placebo at 16 weeks of treatment; the second study ( NCT03776175 ) investigated the effects of PF-05221304 (15 mg twice daily (BID)) co-administered with a DGAT2 inhibitor, PF-06865571 (300 mg BID), versus placebo after 6 weeks of treatment. The primary endpoint in both studies was percent change from baseline in liver fat assessed by magnetic resonance imaging-proton density fat fraction. Dose-dependent reductions in liver fat reached 50-65% with PF-05221304 monotherapy doses ≥10 mg QD; least squares mean (LSM) 80% confidence interval (CI) was -7.2 (-13.9, 0.0), -17.1 (-22.7, -11.1), -49.9 (-53.3, -46.2), -55.9 (-59.0, -52.4) and -64.8 (-67.5, -62.0) with 16 weeks placebo and PF-05221304 2, 10, 25 and 50 mg QD, respectively. The overall incidence of adverse events (AEs) did not increase with increasing PF-05221304 dose, except for a dose-dependent elevation in serum triglycerides (a known consequence of hepatic acetyl-coenzyme A carboxylase (ACC) inhibition) in 23/305 (8%) patients, leading to withdrawal in 13/305 (4%), and a dose-dependent elevation in other serum lipids. Co-administration of PF-05221304 and PF-06865571 lowered liver fat compared to placebo (placebo-adjusted LSM (90% CI) -44.6% (-54.8, -32.2)). Placebo-adjusted LSM (90% CI) reduction in liver fat was -44.5% (-55.0, -31.7) and -35.4% (-47.4, -20.7) after 6 weeks with PF-05221304 or PF-06865571 alone. AEs were reported for 10/28 (36%) patients after co-administered PF-05221304 and PF-06865571, with no discontinuations due to AEs, and the ACC inhibitor-mediated effect on serum triglycerides was mitigated, suggesting that PF-05221304 and PF-06865571 co-administration has the potential to address some of the limitations of ACC inhibition alone.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 10 Oct 2021; epub ahead of print
Calle RA, Amin NB, Carvajal-Gonzalez S, Ross TT, ... Pfefferkorn JA, Esler WP
Nat Med: 10 Oct 2021; epub ahead of print | PMID: 34635855
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Abstract

Powered hip exoskeleton improves walking economy in individuals with above-knee amputation.

Ishmael MK, Archangeli D, Lenzi T
Above-knee amputation severely reduces the mobility and quality of life of millions of individuals. Walking with available leg prostheses is highly inefficient, and poor walking economy is a major problem limiting mobility. Here we show that an autonomous powered hip exoskeleton assisting the residual limb significantly improves metabolic walking economy by 15.6 ± 2.9% (mean ± s.e.m.; two-tailed paired t-test, P = 0.002) in six individuals with above-knee amputation walking on a treadmill. The observed metabolic cost improvement is equivalent to removing a 12-kg backpack from a nonamputee individual. All participants were able to walk overground with the exoskeleton, including starting and stopping, without notable changes in gait balance or stability. This study shows that assistance of the user\'s residual limb with a powered hip exoskeleton is a viable solution for improving amputee walking economy. By significantly reducing the metabolic cost of walking, the proposed hip exoskeleton may have a considerable positive impact on mobility, improving the quality of life of individuals with above-knee amputations.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 10 Oct 2021; epub ahead of print
Ishmael MK, Archangeli D, Lenzi T
Nat Med: 10 Oct 2021; epub ahead of print | PMID: 34635852
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Abstract

Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial.

Stephenson KE, Julg B, Tan CS, Zash R, ... Korber B, Barouch DH
Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg-1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg-1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.

© 2021. The Author(s).

Nat Med: 06 Oct 2021; epub ahead of print
Stephenson KE, Julg B, Tan CS, Zash R, ... Korber B, Barouch DH
Nat Med: 06 Oct 2021; epub ahead of print | PMID: 34621054
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Abstract

Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes.

Sahoo SS, Pastor VB, Goodings C, Voss RK, ... Niemeyer CM, Wlodarski MW
Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 06 Oct 2021; epub ahead of print
Sahoo SS, Pastor VB, Goodings C, Voss RK, ... Niemeyer CM, Wlodarski MW
Nat Med: 06 Oct 2021; epub ahead of print | PMID: 34621053
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Abstract

Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.

Ratziu V, de Guevara L, Safadi R, Poordad F, ... ARREST investigator study group, Sanyal AJ
Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo arms, respectively; NCT02279524 ). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95% confidence interval (CI) -6.4 to 0.2, P = 0.066), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88, 95% CI = 0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for 600 mg was -29.1 IU l-1 (95% CI = -41.6 to -16.5). Early termination due to adverse events (AEs) was <5%, and Aramchol 600 and 400 mg were safe, well tolerated and without imbalance in serious or severe AEs between arms. Although the primary end point of a reduction in liver fat did not meet the prespecified significance level with Aramchol 600 mg, the observed safety and changes in liver histology and enzymes provide a rationale for SCD1 modulation as a promising therapy for NASH and fibrosis and are being evaluated in an ongoing phase 3 program.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 06 Oct 2021; epub ahead of print
Ratziu V, de Guevara L, Safadi R, Poordad F, ... ARREST investigator study group, Sanyal AJ
Nat Med: 06 Oct 2021; epub ahead of print | PMID: 34621052
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Abstract

Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce.

Li Q, Hagberg CE, Silva Cascales H, Lang S, ... Thorell A, Spalding KL
Obesity is considered an important factor for many chronic diseases, including diabetes, cardiovascular disease and cancer. The expansion of adipose tissue in obesity is due to an increase in both adipocyte progenitor differentiation and mature adipocyte cell size. Adipocytes, however, are thought to be unable to divide or enter the cell cycle. We demonstrate that mature human adipocytes unexpectedly display a gene and protein signature indicative of an active cell cycle program. Adipocyte cell cycle progression associates with obesity and hyperinsulinemia, with a concomitant increase in cell size, nuclear size and nuclear DNA content. Chronic hyperinsulinemia in vitro or in humans, however, is associated with subsequent cell cycle exit, leading to a premature senescent transcriptomic and secretory profile in adipocytes. Premature senescence is rapidly becoming recognized as an important mediator of stress-induced tissue dysfunction. By demonstrating that adipocytes can activate a cell cycle program, we define a mechanism whereby mature human adipocytes senesce. We further show that by targeting the adipocyte cell cycle program using metformin, it is possible to influence adipocyte senescence and obesity-associated adipose tissue inflammation.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 03 Oct 2021; epub ahead of print
Li Q, Hagberg CE, Silva Cascales H, Lang S, ... Thorell A, Spalding KL
Nat Med: 03 Oct 2021; epub ahead of print | PMID: 34608330
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Abstract

Immune responses to two and three doses of the BNT162b2 mRNA vaccine in adults with solid tumors.

Shroff RT, Chalasani P, Wei R, Pennington D, ... LaFleur BJ, Bhattacharya D
Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have shown high efficacy, but immunocompromised participants were excluded from controlled clinical trials. In this study, we compared immune responses to the BNT162b2 mRNA Coronavirus Disease 2019 vaccine in patients with solid tumors (n = 53) who were on active cytotoxic anti-cancer therapy to a control cohort of participants without cancer (n = 50). Neutralizing antibodies were detected in 67% of patients with cancer after the first immunization, followed by a threefold increase in median titers after the second dose. Similar patterns were observed for spike protein-specific serum antibodies and T cells, but the magnitude of each of these responses was diminished relative to the control cohort. In most patients with cancer, we detected spike receptor-binding domain and other S1-specific memory B cell subsets as potential predictors of anamnestic responses to additional immunizations. We therefore initiated a phase 1 trial for 20 cancer cohort participants of a third vaccine dose of BNT162b2 ( NCT04936997 ); primary outcomes were immune responses, with a secondary outcome of safety. At 1 week after a third immunization, 16 participants demonstrated a median threefold increase in neutralizing antibody responses, but no improvement was observed in T cell responses. Adverse events were mild. These results suggest that a third dose of BNT162b2 is safe, improves humoral immunity against SARS-CoV-2 and could be immunologically beneficial for patients with cancer on active chemotherapy.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Sep 2021; epub ahead of print
Shroff RT, Chalasani P, Wei R, Pennington D, ... LaFleur BJ, Bhattacharya D
Nat Med: 29 Sep 2021; epub ahead of print | PMID: 34594036
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Abstract

Immunogenicity and safety of the CoronaVac inactivated vaccine in patients with autoimmune rheumatic diseases: a phase 4 trial.

Medeiros-Ribeiro AC, Aikawa NE, Saad CGS, Yuki EFN, ... Pasoto SG, Bonfa E
CoronaVac, an inactivated SARS-CoV-2 vaccine, has been approved for emergency use in several countries. However, its immunogenicity in immunocompromised individuals has not been well established. We initiated a prospective phase 4 controlled trial (no. NCT04754698, CoronavRheum) in 910 adults with autoimmune rheumatic diseases (ARD) and 182 age- and sex-frequency-matched healthy adults (control group, CG), who received two doses of CoronaVac. The primary outcomes were reduction of ≥15% in both anti-SARS-CoV-2 IgG seroconversion (SC) and neutralizing antibody (NAb) positivity 6 weeks (day 69 (D69)) after the second dose in the ARD group compared with that in the CG. Secondary outcomes were IgG SC and NAb positivity at D28, IgG titers and neutralizing activity at D28 and D69 and vaccine safety. Prespecified endpoints were met, with lower anti-SARS-Cov-2 IgG SC (70.4 versus 95.5%, P < 0.001) and NAb positivity (56.3 versus 79.3%, P < 0.001) at D69 in the ARD group than in the CG. Moreover, IgG titers (12.1 versus 29.7, P < 0.001) and median neutralization activity (58.7 versus 64.5%, P = 0.013) were also lower at D69 in patients with ARD. At D28, patients with ARD presented with lower IgG frequency (18.7 versus 34.6%, P < 0.001) and NAb positivity (20.6 versus 36.3%, P < 0.001) than that of the CG. There were no moderate/severe adverse events. These data support the use of CoronaVac in patients with ARD, suggesting reduced but acceptable short-term immunogenicity. The trial is still ongoing to evaluate the long-term effectiveness/immunogenicity.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Sep 2021; 27:1744-1751
Medeiros-Ribeiro AC, Aikawa NE, Saad CGS, Yuki EFN, ... Pasoto SG, Bonfa E
Nat Med: 29 Sep 2021; 27:1744-1751 | PMID: 34331051
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Abstract

Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial.

Kyriazopoulou E, Poulakou G, Milionis H, Metallidis S, ... Dalekos GN, Giamarellos-Bourboulis EJ
Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/β inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml-1, 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.

© 2021. The Author(s).

Nat Med: 29 Sep 2021; 27:1752-1760
Kyriazopoulou E, Poulakou G, Milionis H, Metallidis S, ... Dalekos GN, Giamarellos-Bourboulis EJ
Nat Med: 29 Sep 2021; 27:1752-1760 | PMID: 34480127
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Abstract

Effectiveness of the BNT162b2 mRNA COVID-19 vaccine in pregnancy.

Dagan N, Barda N, Biron-Shental T, Makov-Assif M, ... Reis BY, Balicer RD
To evaluate the effectiveness of the BNT162b2 messenger RNA vaccine in pregnant women, we conducted an observational cohort study of pregnant women aged 16 years or older, with no history of SARS-CoV-2, who were vaccinated between 20 December 2020 and 3 June 2021. A total of 10,861 vaccinated pregnant women were matched to 10,861 unvaccinated pregnant controls using demographic and clinical characteristics. Study outcomes included documented infection with SARS-CoV-2, symptomatic COVID-19, COVID-19-related hospitalization, severe illness and death. Estimated vaccine effectiveness from 7 through to 56 d after the second dose was 96% (95% confidence interval 89-100%) for any documented infection, 97% (91-100%) for infections with documented symptoms and 89% (43-100%) for COVID-19-related hospitalization. Only one event of severe illness was observed in the unvaccinated group and no deaths were observed in either group. In summary, the BNT162b2 mRNA vaccine was estimated to have high vaccine effectiveness in pregnant women, which is similar to the effectiveness estimated in the general population.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Sep 2021; 27:1693-1695
Dagan N, Barda N, Biron-Shental T, Makov-Assif M, ... Reis BY, Balicer RD
Nat Med: 29 Sep 2021; 27:1693-1695 | PMID: 34493859
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Abstract

Federated learning for predicting clinical outcomes in patients with COVID-19.

Dayan I, Roth HR, Zhong A, Harouni A, ... Flores MG, Li Q
Federated learning (FL) is a method used for training artificial intelligence models with data from multiple sources while maintaining data anonymity, thus removing many barriers to data sharing. Here we used data from 20 institutes across the globe to train a FL model, called EXAM (electronic medical record (EMR) chest X-ray AI model), that predicts the future oxygen requirements of symptomatic patients with COVID-19 using inputs of vital signs, laboratory data and chest X-rays. EXAM achieved an average area under the curve (AUC) >0.92 for predicting outcomes at 24 and 72 h from the time of initial presentation to the emergency room, and it provided 16% improvement in average AUC measured across all participating sites and an average increase in generalizability of 38% when compared with models trained at a single site using that site\'s data. For prediction of mechanical ventilation treatment or death at 24 h at the largest independent test site, EXAM achieved a sensitivity of 0.950 and specificity of 0.882. In this study, FL facilitated rapid data science collaboration without data exchange and generated a model that generalized across heterogeneous, unharmonized datasets for prediction of clinical outcomes in patients with COVID-19, setting the stage for the broader use of FL in healthcare.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Sep 2021; 27:1735-1743
Dayan I, Roth HR, Zhong A, Harouni A, ... Flores MG, Li Q
Nat Med: 29 Sep 2021; 27:1735-1743 | PMID: 34526699
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Abstract

Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.

Ho CY, Day SM, Axelsson A, Russell MW, ... Orav EJ, Braunwald E
Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80-160 mg daily in children) or placebo for 2 years ( NCT01912534 ). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Sep 2021; 27:1818-1824
Ho CY, Day SM, Axelsson A, Russell MW, ... Orav EJ, Braunwald E
Nat Med: 29 Sep 2021; 27:1818-1824 | PMID: 34556856
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Abstract

Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue.

Thomsen G, Burghes AHM, Hsieh C, Do J, ... Mendell JR, Foust KD
Spinal muscular atrophy type 1 (SMA1) is a debilitating neurodegenerative disease resulting from survival motor neuron 1 gene (SMN1) deletion/mutation. Onasemnogene abeparvovec (formerly AVXS-101) is a gene therapy that restores SMN production via one-time systemic administration. The present study demonstrates widespread biodistribution of vector genomes and transgenes throughout the central nervous system (CNS) and peripheral organs, after intravenous administration of an AAV9-mediated gene therapy. Two symptomatic infants with SMA1 enrolled in phase III studies received onasemnogene abeparvovec. Both patients died of respiratory complications unrelated to onasemnogene abeparvovec. One patient had improved motor function and the other died shortly after administration before appreciable clinical benefit could be observed. In both patients, onasemnogene abeparvovec DNA and messenger RNA distribution were widespread among peripheral organs and in the CNS. The greatest concentration of vector genomes was detected in the liver, with an increase over that detected in CNS tissues of 300-1,000-fold. SMN protein, which was low in an untreated SMA1 control, was clearly detectable in motor neurons, brain, skeletal muscle and multiple peripheral organs in treated patients. These data support the fact that onasemnogene abeparvovec has effective distribution, transduction and expression throughout the CNS after intravenous administration and restores SMN expression in humans.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Sep 2021; 27:1701-1711
Thomsen G, Burghes AHM, Hsieh C, Do J, ... Mendell JR, Foust KD
Nat Med: 29 Sep 2021; 27:1701-1711 | PMID: 34608334
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Abstract

Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB-IVM1a melanoma: a randomized, open-label, phase 2 trial.

Dummer R, Gyorki DE, Hyngstrom J, Berger AC, ... Faries M, Ross MI
Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-based intralesional oncolytic immunotherapy approved for the treatment of unresectable melanoma. The present, ongoing study aimed to estimate the treatment effect of neoadjuvant T-VEC on recurrence-free survival (RFS) of patients with advanced resectable melanoma. An open-label, phase 2 trial (NCT02211131) was conducted in 150 patients with resectable stage IIIB-IVM1a melanoma who were randomized to receive T-VEC followed by surgery (arm 1, n = 76) or surgery alone (arm 2, n = 74). The primary endpoint was a 2-year RFS in the intention-to-treat population. Secondary and exploratory endpoints included overall survival (OS), pathological complete response (pCR), safety and biomarker analyses. The 2-year RFS was 29.5% in arm 1 and 16.5% in arm 2 (overall hazard ratio (HR) = 0.75, 80% confidence interval (CI) = 0.58-0.96). The 2-year OS was 88.9% for arm 1 and 77.4% for arm 2 (overall HR = 0.49, 80% CI = 0.30-0.79). The RFS and OS differences between arms persisted at 3 years. In arm 1, 17.1% achieved a pCR. Increased CD8+ density correlated with clinical outcomes in an exploratory analysis. Arm 1 adverse events were consistent with previous reports for T-VEC. The present study met its primary endpoint and estimated a 25% reduction in the risk of disease recurrence for neoadjuvant T-VEC plus surgery versus upfront surgery for patients with resectable stage IIIB-IVM1a melanoma.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Sep 2021; 27:1789-1796
Dummer R, Gyorki DE, Hyngstrom J, Berger AC, ... Faries M, Ross MI
Nat Med: 29 Sep 2021; 27:1789-1796 | PMID: 34608333
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Abstract

Safety and pharmacokinetics of islatravir subdermal implant for HIV-1 pre-exposure prophylaxis: a randomized, placebo-controlled phase 1 trial.

Matthews RP, Patel M, Barrett SE, Haspeslagh L, ... Stoch SA, Iwamoto M
Islatravir (MK-8591) is a highly potent type 1 human immunodeficiency virus (HIV-1) nucleoside reverse transcriptase translocation inhibitor with a long intracellular half-life that is in development for the prevention and treatment of HIV-1. We conducted a randomized, double-blind, placebo-controlled, phase 1 trial in adults without HIV-1 infection. Participants received islatravir or placebo subdermal implants for 12 weeks and were monitored throughout this period and after implant removal. The co-primary end points were safety and tolerability of the islatravir implant and pharmacokinetics, including concentration at day 85, of islatravir triphosphate in peripheral blood mononuclear cells (PBMCs). Secondary end points included additional pharmacokinetic parameters for islatravir triphosphate in PBMCs and the plasma pharmacokinetic profile of islatravir. Based on preclinical data, two doses were assessed: 54 mg (n = 8, two placebo) and 62 mg (n = 8, two placebo). The most frequently reported adverse events were mild-to-moderate implant-site reactions (induration, hematoma, pain). Throughout the 12-week trial, geometric mean islatravir triphosphate concentrations were above a pharmacokinetic threshold of 0.05 pmol per 106 PBMCs, which was estimated to provide therapeutic reverse transcriptase inhibition (concentration at day 85 (percentage of geometric coefficient of variation): 54 mg, 0.135 pmol per 106 cells (27.3); 62 mg, 0.272 pmol per 106 cells (45.2)). Islatravir implants at both doses were safe and resulted in mean concentrations above the pharmacokinetic threshold through 12 weeks, warranting further investigation of islatravir implants as a potential HIV prevention strategy.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Sep 2021; 27:1712-1717
Matthews RP, Patel M, Barrett SE, Haspeslagh L, ... Stoch SA, Iwamoto M
Nat Med: 29 Sep 2021; 27:1712-1717 | PMID: 34608329
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Abstract

Closed-loop neuromodulation in an individual with treatment-resistant depression.

Scangos KW, Khambhati AN, Daly PM, Makhoul GS, ... Krystal AD, Chang EF
Deep brain stimulation is a promising treatment for neuropsychiatric conditions such as major depression. It could be optimized by identifying neural biomarkers that trigger therapy selectively when symptom severity is elevated. We developed an approach that first used multi-day intracranial electrophysiology and focal electrical stimulation to identify a personalized symptom-specific biomarker and a treatment location where stimulation improved symptoms. We then implanted a chronic deep brain sensing and stimulation device and implemented a biomarker-driven closed-loop therapy in an individual with depression. Closed-loop therapy resulted in a rapid and sustained improvement in depression. Future work is required to determine if the results and approach of this n-of-1 study generalize to a broader population.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Nat Med: 29 Sep 2021; 27:1696-1700
Scangos KW, Khambhati AN, Daly PM, Makhoul GS, ... Krystal AD, Chang EF
Nat Med: 29 Sep 2021; 27:1696-1700 | PMID: 34608328
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Abstract

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

Feng S, Phillips DJ, White T, Sayal H, ... Voysey M, Oxford COVID Vaccine Trial Group
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.

© 2021. The Author(s).

Nat Med: 28 Sep 2021; epub ahead of print
Feng S, Phillips DJ, White T, Sayal H, ... Voysey M, Oxford COVID Vaccine Trial Group
Nat Med: 28 Sep 2021; epub ahead of print | PMID: 34588689
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Abstract

Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis.

Choi A, Koch M, Wu K, Chu L, ... McPhee R, Edwards DK
The emergence of SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) with decreased susceptibility to neutralization has generated interest in assessments of booster doses and variant-specific vaccines. Clinical trial participants who received a two-dose primary series of the COVID-19 vaccine mRNA-1273 approximately 6 months earlier entered an open-label phase 2a study ( NCT04405076 ) to evaluate the primary objectives of safety and immunogenicity of a single booster dose of mRNA-1273 or variant-modified mRNAs, including multivalent mRNA-1273.211. As the trial is currently ongoing, this exploratory interim analysis includes preliminary descriptive results only of four booster groups (n = 20 per group). Immediately before the booster dose, neutralizing antibodies against wild-type D614G virus had waned (P < 0.0001) relative to peak titers against wild-type D614G measured 1 month after the primary series, and neutralization titers against B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) VOCs were either low or undetectable. Both the mRNA-1273 booster and variant-modified boosters were safe and well-tolerated. All boosters, including mRNA-1273, numerically increased neutralization titers against the wild-type D614G virus compared to peak titers against wild-type D614G measured 1 month after the primary series; significant increases were observed for mRNA-1273 and mRNA-1273.211 (P < 0.0001). In addition, all boosters increased neutralization titers against key VOCs and VOIs, including B.1.351, P.1. and B.1.617.2, that were statistically equivalent to peak titers measured after the primary vaccine series against wild-type D614G virus, with superior titers against some VOIs. This trial is ongoing.

© 2021. The Author(s).

Nat Med: 14 Sep 2021; epub ahead of print
Choi A, Koch M, Wu K, Chu L, ... McPhee R, Edwards DK
Nat Med: 14 Sep 2021; epub ahead of print | PMID: 34526698
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Abstract

Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy.

Apostolidis SA, Kakara M, Painter MM, Goel RR, ... Li R, Bar-Or A
SARS-CoV-2 messenger RNA vaccination in healthy individuals generates immune protection against COVID-19. However, little is known about SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed patients. We investigated induction of antigen-specific antibody, B cell and T cell responses longitudinally in patients with multiple sclerosis (MS) on anti-CD20 antibody monotherapy (n = 20) compared with healthy controls (n = 10) after BNT162b2 or mRNA-1273 mRNA vaccination. Treatment with anti-CD20 monoclonal antibody (aCD20) significantly reduced spike-specific and receptor-binding domain (RBD)-specific antibody and memory B cell responses in most patients, an effect ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution. By contrast, all patients with MS treated with aCD20 generated antigen-specific CD4 and CD8 T cell responses after vaccination. Treatment with aCD20 skewed responses, compromising circulating follicular helper T (TFH) cell responses and augmenting CD8 T cell induction, while preserving type 1 helper T (TH1) cell priming. Patients with MS treated with aCD20 lacking anti-RBD IgG had the most severe defect in circulating TFH responses and more robust CD8 T cell responses. These data define the nature of the SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients and provide insights into coordinated mRNA vaccine-induced immune responses in humans. Our findings have implications for clinical decision-making and public health policy for immunosuppressed patients including those treated with aCD20.

© 2021. The Author(s).

Nat Med: 13 Sep 2021; epub ahead of print
Apostolidis SA, Kakara M, Painter MM, Goel RR, ... Li R, Bar-Or A
Nat Med: 13 Sep 2021; epub ahead of print | PMID: 34522051
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Abstract

Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial.

Bégin P, Callum J, Jamula E, Cook R, ... CONCOR-1 Study Group, Arnold DM
The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset ( NCT04348656 ). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm-relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94-1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02-1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57-0.95 and OR = 0.66, 95% CI 0.50-0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14-2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.

© 2021. The Author(s).

Nat Med: 08 Sep 2021; epub ahead of print
Bégin P, Callum J, Jamula E, Cook R, ... CONCOR-1 Study Group, Arnold DM
Nat Med: 08 Sep 2021; epub ahead of print | PMID: 34504336
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Impact:
Abstract

Predictors of COVID-19 epidemics in countries of the World Health Organization African Region.

Zhang F, Karamagi H, Nsenga N, Nanyunja M, ... Moeti MR, Woolhouse MEJ
Countries of the World Health Organization (WHO) African Region have experienced a wide range of coronavirus disease 2019 (COVID-19) epidemics. This study aimed to identify predictors of the timing of the first COVID-19 case and the per capita mortality in WHO African Region countries during the first and second pandemic waves and to test for associations with the preparedness of health systems and government pandemic responses. Using a region-wide, country-based observational study, we found that the first case was detected earlier in countries with more urban populations, higher international connectivity and greater COVID-19 test capacity but later in island nations. Predictors of a high first wave per capita mortality rate included a more urban population, higher pre-pandemic international connectivity and a higher prevalence of HIV. Countries rated as better prepared and having more resilient health systems were worst affected by the disease, the imposition of restrictions or both, making any benefit of more stringent countermeasures difficult to detect. Predictors for the second wave were similar to the first. Second wave per capita mortality could be predicted from that of the first wave. The COVID-19 pandemic highlights unanticipated vulnerabilities to infectious disease in Africa that should be taken into account in future pandemic preparedness planning.

© 2021. The Author(s).

Nat Med: 02 Sep 2021; epub ahead of print
Zhang F, Karamagi H, Nsenga N, Nanyunja M, ... Moeti MR, Woolhouse MEJ
Nat Med: 02 Sep 2021; epub ahead of print | PMID: 34480125
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Impact:

This program is still in alpha version.