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1.
PNAS Nexus ; 1(3): pgac091, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1961140

ABSTRACT

Emergence of SARS-CoV-2 variants and waning of vaccine/infection-induced immunity pose threats to curbing the COVID-19 pandemic. Effective, safe, and convenient booster vaccines are in need. We hypothesized that a variant-modified mucosal booster vaccine might induce local immunity to prevent SARS-CoV-2 infection at the port of entry. The beta-variant is one of the hardest to cross-neutralize. Herein, we assessed the protective efficacy of an intranasal booster composed of beta variant-spike protein S1 with IL-15 and TLR agonists in previously immunized macaques. The macaques were first vaccinated with Wuhan strain S1 with the same adjuvant. A total of 1 year later, negligibly detectable SARS-CoV-2-specific antibody remained. Nevertheless, the booster induced vigorous humoral immunity including serum- and bronchoalveolar lavage (BAL)-IgG, secretory nasal- and BAL-IgA, and neutralizing antibody against the original strain and/or beta variant. Beta-variant S1-specific CD4+ and CD8+ T cell responses were also elicited in PBMC and BAL. Following SARS-CoV-2 beta variant challenge, the vaccinated group demonstrated significant protection against viral replication in the upper and lower respiratory tracts, with almost full protection in the nasal cavity. The fact that one intranasal beta-variant booster administrated 1 year after the first vaccination provoked protective immunity against beta variant infections may inform future SARS-CoV-2 booster design and administration timing.

2.
BMC Genomics ; 23(1): 513, 2022 Jul 15.
Article in English | MEDLINE | ID: covidwho-1938288

ABSTRACT

BACKGROUND: With the emergence and spread of SARS-CoV-2 variants, genomic epidemiology and surveillance have proven invaluable tools for variant tracking. Here, we analyzed SARS-CoV-2 samples collected from personnel located at the US/NATO bases across Afghanistan. RESULTS: Sequencing and phylogenetic analyses revealed at least 16 independent introductions of SARS-CoV-2 into four of these relatively isolated compounds during April and May 2021, including multiple introductions of Alpha and Delta variants. Four of the introductions resulted in sustained spread of the virus within, and in two cases between, the compounds. Three of these outbreaks, one Delta and two Alpha, occurred simultaneously. CONCLUSIONS: Even in rigorously controlled and segregated environments, SARS-CoV-2 introduction and spread may occur frequently.


Subject(s)
COVID-19 , Military Personnel , Afghanistan/epidemiology , COVID-19/epidemiology , Disease Outbreaks , Genomics , Humans , Phylogeny , SARS-CoV-2/genetics
3.
JMIR Med Inform ; 10(7): e39145, 2022 Jul 08.
Article in English | MEDLINE | ID: covidwho-1933494

ABSTRACT

Electronic health record (EHR) technology has become a central digital health tool throughout health care. EHR systems are responsible for a growing number of vital functions for hospitals and providers. More recently, patient-facing EHR tools are allowing patients to interact with their EHR and connect external sources of health data, such as wearable fitness trackers, personal genomics, and outside health services, to it. As patients become more engaged with their EHR, the volume and variety of digital health information will serve an increasingly useful role in health care and health research. Particularly due to the COVID-19 pandemic, the ability for the biomedical research community to pivot to fully remote research, driven largely by EHR data capture and other digital health tools, is an exciting development that can significantly reduce burden on study participants, improve diversity in clinical research, and equip researchers with more robust clinical data. In this viewpoint, we describe how patient engagement with EHR technology is poised to advance the digital clinical trial space, an innovative research model that is uniquely accessible and inclusive for study participants.

4.
Nat Biotechnol ; 40(7): 1013-1022, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1900500

ABSTRACT

At the beginning of the COVID-19 pandemic, analog tools such as nasopharyngeal swabs for PCR tests were center stage and the major prevention tactics of masking and physical distancing were a throwback to the 1918 influenza pandemic. Overall, there has been scant regard for digital tools, particularly those based on smartphone apps, which is surprising given the ubiquity of smartphones across the globe. Smartphone apps, given accessibility in the time of physical distancing, were widely used for tracking, tracing and educating the public about COVID-19. Despite limitations, such as concerns around data privacy, data security, digital health illiteracy and structural inequities, there is ample evidence that apps are beneficial for understanding outbreak epidemiology, individual screening and contact tracing. While there were successes and failures in each category, outbreak epidemiology and individual screening were substantially enhanced by the reach of smartphone apps and accessory wearables. Continued use of apps within the digital infrastructure promises to provide an important tool for rigorous investigation of outcomes both in the ongoing outbreak and in future epidemics.


Subject(s)
COVID-19 , Mobile Applications , COVID-19/epidemiology , Contact Tracing , Humans , Pandemics/prevention & control , SARS-CoV-2/genetics
5.
Genetics in Medicine ; 24(3):S312-S313, 2022.
Article in English | Web of Science | ID: covidwho-1867161
6.
Kidney360 ; 2(7): 1179-1187, 2021 07 29.
Article in English | MEDLINE | ID: covidwho-1776845

ABSTRACT

COVID-19 has significantly affected the transplant community, by leading to decreased transplant activity and increased waiting list time. As expected, COVID-19 causes substantial mortality in both ESKD and kidney transplant populations. This is due to underlying CKD and a high prevalence of comorbid conditions, such as diabetes mellitus, hypertension, and cardiovascular disease in this group. Transplant programs have faced the difficult decision of weighing the risks and benefits of transplantation during the pandemic. On one hand, there is a risk of COVID-19 exposure leading to infection while patients are on maximum immunosuppression. Alternatively, there are risks of delaying transplantation, which will increase waitlist times and may lead to waitlist-associated morbidity and mortality. Cautious and thoughtful selection of both the recipient's and donor's post-transplant management has been required during the pandemic, to mitigate the risk of morbidity and mortality associated with COVID-19. In this review article, we aimed to discuss previous publications related to clinical outcomes of COVID-19 disease in kidney transplant recipients, patients with ESKD on dialysis, or on the transplant waiting list, and the precautions transplant centers should take in decision making for recipient and donor selection and immunosuppressive management during the pandemic. Nevertheless, transplantation in this milieu does seem to be the correct decision, with careful patient and donor selection and safeguard protocols for infection prevention. Each center should conduct risk assessment on the basis of the patient's age and medical comorbidities, waitlist time, degree of sensitization, cold ischemia time, status of vaccination, and severity of pandemic in their region.


Subject(s)
COVID-19 , Kidney Transplantation , COVID-19/epidemiology , Humans , Kidney Transplantation/adverse effects , Pandemics , Renal Dialysis , Risk Assessment , SARS-CoV-2
8.
N Engl J Med ; 386(6): 509-520, 2022 02 10.
Article in English | MEDLINE | ID: covidwho-1574650

ABSTRACT

BACKGROUND: New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29. RESULTS: A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, -6.8 percentage points; 95% confidence interval [CI], -11.3 to -2.4; P = 0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, -3.0 percentage points; 95% CI, -5.9 to -0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group. CONCLUSIONS: Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.).


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytidine/analogs & derivatives , Hydroxylamines/therapeutic use , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Antiviral Agents/adverse effects , COVID-19/virology , Cytidine/adverse effects , Cytidine/therapeutic use , Double-Blind Method , Female , Humans , Hydroxylamines/adverse effects , Male , Middle Aged , SARS-CoV-2/isolation & purification , Treatment Outcome , Viral Load , Young Adult
9.
Open forum infectious diseases ; 8(Suppl 1):S554-S555, 2021.
Article in English | EuropePMC | ID: covidwho-1564936

ABSTRACT

Background Chimeric antigen receptor (CAR-T) T-cell therapy is a novel immunotherapy for cancer treatment in which patients are treated with targeted, genetically-modified T-cells. Common side effects include cytokine release syndrome, neurotoxicity, hypogammaglobulinemia, and increased susceptibility to infections. Long-term infectious outcomes are poorly characterized. Methods We retrospectively examined patients who received CAR-T therapy at BIDMC & MGH from July 2016 to March 2020 and evaluated bacterial, fungal, viral, and parasitic infections at 3 months intervals to 1 year following cell infusion. The incidence, timing, and outcomes of the infectious complications were evaluated. Results In total, there were 47 patients;averaging 61.4 years of age (±12 years). Primary indications for CAR-T therapy included diffuse large b-cell lymphoma (65%) and multiple myeloma (25%), chronic lymphocytic leukemia (2%) and mantle cell lymphoma (2%). Patients had received an average 4 ± 2.9 lines of chemotherapy prior to CAR-T infusion;19 subjects (40%) had a history of prior autologous stem cell transplant. All patients received acyclovir for antiviral prophylaxis and most received either trimethoprim-sulfamethoxazole (24/47;51%) or atovaquone (16/47;34%) for pneumocystis prophylaxis. In the first year, 35/47 (74.5%) of subjects experienced at least one infection with an infection rate of 84.4/10,000 person days. Median time to first infection was 59 days (range 1-338 patient days). 31/47 (66.0%) subjects had at least one bacterial infection, with pulmonary (42/113;37.2%) sources being the most common site of infection. 13/47 (27.7%) of patients had a viral infection (predominantly respiratory viral infections) and 6/47 (12.8%) had a proven or probable fungal infection. Death attributed to infection was noted in 2 subjects (4.3%), both related to COVID-19. Baseline IgG levels were significantly lower in the group with infections (p=0.028), while white blood cell count and absolute neutrophil counts were comparable. Table 1. Baseline Demographic, Clinical Characteristics, and Outcomes of 47 Recipients of CAR-T Cell Therapy by Infection Status Notes BMI: body mass index;DLBCL: diffuse large B-cell lymphoma;CLL: chronic lymphocytic leukemia;Flu/Cy: Fludarabine/cyclophosphamide;IVIG: intravenous immunoglobulin;WBC: white blood cell count;ANC: absolute neutrophil count;ALC: absolute lymphocyte count. Table 2. Characteristics of the 113 Infections in the 35 Subjects Who Developed Infections Conclusion Infectious complications, particularly of bacterial etiology, are common in the first year following CAR-T therapy. These data may inform future prophylactic strategies in this patient population. Disclosures Matthew Frigault, MD, Arcellx (Consultant)BMS (Consultant)Iovance (Consultant)Kite (Consultant)Novartis (Consultant) Jay A. Fishman, MD, Nothing to disclose Jon Arnason, MD, BMS/Juno (Advisor or Review Panel member)Regeneron (Advisor or Review Panel member)

10.
Open Forum Infect Dis ; 8(11): ofab464, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1528169

ABSTRACT

BACKGROUND: We aimed to evaluate a testing program to facilitate control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission at a large university and measure spread in the university community using viral genome sequencing. METHODS: Our prospective longitudinal study used remote contactless enrollment, daily mobile symptom and exposure tracking, and self-swab sample collection. Individuals were tested if the participant was exposed to a known SARS-CoV-2-infected person, developed new symptoms, or reported high-risk behavior (such as attending an indoor gathering without masking or social distancing), if a member of a group experiencing an outbreak, or at enrollment. Study participants included students, staff, and faculty at an urban public university during the Autumn quarter of 2020. RESULTS: We enrolled 16 476 individuals, performed 29 783 SARS-CoV-2 tests, and detected 236 infections. Seventy-five percent of positive cases reported at least 1 of the following: symptoms (60.8%), exposure (34.7%), or high-risk behaviors (21.5%). Greek community affiliation was the strongest risk factor for testing positive, and molecular epidemiology results suggest that specific large gatherings were responsible for several outbreaks. CONCLUSIONS: A testing program focused on individuals with symptoms and unvaccinated persons who participate in large campus gatherings may be effective as part of a comprehensive university-wide mitigation strategy to control the spread of SARS-CoV-2.

11.
Front Immunol ; 12: 737406, 2021.
Article in English | MEDLINE | ID: covidwho-1450813

ABSTRACT

IL-7/IL-7R signaling is critical for development, maturation, maintenance and survival of many lymphocytes in the thymus and periphery. IL-7 has been used as immunotherapy in pre-clinical and clinical studies to treat cancer, HIV infection and sepsis. Here, we discuss the critical function of IL-7 in diagnosis, prognosis and treatment of COVID-19 patients. We also summarize a promising role of IL-7 as a vaccine adjuvant. It could potentially enhance the immune responses to vaccines especially against SARS-CoV-2 or other new vaccines.


Subject(s)
Adjuvants, Immunologic , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Interleukin-7/immunology , SARS-CoV-2/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Humans , Immunogenicity, Vaccine/immunology , Interleukin-7/metabolism , Receptors, Interleukin-7/metabolism
12.
Front Immunol ; 12: 658428, 2021.
Article in English | MEDLINE | ID: covidwho-1389178

ABSTRACT

SARS-CoV-2 virus causes upper and lower respiratory diseases including pneumonia, and in some cases, leads to lethal pulmonary failure. Angiotensin converting enzyme-2 (ACE2), the receptor for cellular entry of SARS-CoV-2 virus, has been shown to protect against severe acute lung failure. Here, we provide evidence that SARS-CoV-2 spike protein S1 reduced the mRNA expression of ACE2 and type I interferons in primary cells of lung bronchoalveolar lavage (BAL) from naïve rhesus macaques. The expression levels of ACE2 and type I interferons were also found to be correlated with each other, consistent with the recent finding that ACE2 is an interferon-inducible gene. Furthermore, induction of ACE2 and type I interferons by poly I:C, an interferon inducer, was suppressed by S1 protein in primary cells of BAL. These observations suggest that the downregulation of ACE2 and type I interferons induced by S1 protein may directly contribute to SARS-CoV-2-associated lung diseases.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 , Interferon Type I/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Animals , Bronchoalveolar Lavage Fluid/cytology , Macaca mulatta , SARS-CoV-2
14.
J Public Health (Oxf) ; 43(3): e553-e554, 2021 09 22.
Article in English | MEDLINE | ID: covidwho-1238234

ABSTRACT

In a recent correspondence, authors discussed the role of private companies in fulfilling their corporate social responsibility (CSR) by coming up with their own vaccination program for their employees during the COVID-19 pandemic. This paper supports the invitation for companies to act in accordance with their CSR and by emphasizing the various roles of companies just like what selected hotels do as isolation and quarantine facilities during the pandemic. However, certain considerations and issues must also be addressed by hotel sectors in accomplishing their CSR especially in time of public health crisis.


Subject(s)
COVID-19 , Pandemics , Humans , Leisure Activities , Pandemics/prevention & control , Quarantine , SARS-CoV-2 , Social Responsibility
15.
JCI Insight ; 6(10)2021 04 28.
Article in English | MEDLINE | ID: covidwho-1206097

ABSTRACT

Effective SARS-CoV-2 vaccines are urgently needed. Although most vaccine strategies have focused on systemic immunization, here we compared the protective efficacy of 2 adjuvanted subunit vaccines with spike protein S1: an intramuscularly primed/boosted vaccine and an intramuscularly primed/intranasally boosted mucosal vaccine in rhesus macaques. The intramuscular-alum-only vaccine induced robust binding and neutralizing antibody and persistent cellular immunity systemically and mucosally, whereas intranasal boosting with nanoparticles, including IL-15 and TLR agonists, elicited weaker T cell and Ab responses but higher dimeric IgA and IFN-α. Nevertheless, following SARS-CoV-2 challenge, neither group showed detectable subgenomic RNA in upper or lower respiratory tracts versus naive controls, indicating full protection against viral replication. Although mucosal and systemic protective mechanisms may differ, results demonstrate both vaccines can protect against respiratory SARS-CoV-2 exposure. In summary, we have demonstrated that the mucosal vaccine was safe after multiple doses and cleared the input virus more efficiently in the nasal cavity and thus may act as a potent complementary reinforcing boost for conventional systemic vaccines to provide overall better protection.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/veterinary , Macaca mulatta/immunology , SARS-CoV-2/immunology , Adaptive Immunity , Animals , Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19/pathology , COVID-19/prevention & control , Humans , Immunity, Cellular , Immunity, Humoral , Vaccines, Subunit/therapeutic use
16.
Proc Natl Acad Sci U S A ; 118(15)2021 04 13.
Article in English | MEDLINE | ID: covidwho-1152940

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research and antiviral discovery are hampered by the lack of a cell-based virus replication system that can be readily adopted without biosafety level 3 (BSL-3) restrictions. Here, the construction of a noninfectious SARS-CoV-2 reporter replicon and its application in deciphering viral replication mechanisms and evaluating SARS-CoV-2 inhibitors are presented. The replicon genome is replication competent but does not produce progeny virions. Its replication can be inhibited by RdRp mutations or by known SARS-CoV-2 antiviral compounds. Using this system, a high-throughput antiviral assay has also been developed. Significant differences in potencies of several SARS-CoV-2 inhibitors in different cell lines were observed, which highlight the challenges of discovering antivirals capable of inhibiting viral replication in vivo and the importance of testing compounds in multiple cell culture models. The generation of a SARS-CoV-2 replicon provides a powerful platform to expand the global research effort to combat COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/virology , High-Throughput Screening Assays/methods , Replicon/drug effects , SARS-CoV-2/drug effects , A549 Cells , Animals , Chlorocebus aethiops , Coronavirus RNA-Dependent RNA Polymerase/genetics , HEK293 Cells , Humans , Replicon/genetics , SARS-CoV-2/genetics , Vero Cells , Virus Replication/drug effects
17.
Transpl Int ; 34(6): 1019-1031, 2021 06.
Article in English | MEDLINE | ID: covidwho-1140311

ABSTRACT

The increasing global prevalence of SARS-CoV-2 and the resulting COVID-19 disease pandemic pose significant concerns for clinical management of solid organ transplant recipients (SOTR). Wearable devices that can measure physiologic changes in biometrics including heart rate, heart rate variability, body temperature, respiratory, activity (such as steps taken per day) and sleep patterns, and blood oxygen saturation show utility for the early detection of infection before clinical presentation of symptoms. Recent algorithms developed using preliminary wearable datasets show that SARS-CoV-2 is detectable before clinical symptoms in >80% of adults. Early detection of SARS-CoV-2, influenza, and other pathogens in SOTR, and their household members, could facilitate early interventions such as self-isolation and early clinical management of relevant infection(s). Ongoing studies testing the utility of wearable devices such as smartwatches for early detection of SARS-CoV-2 and other infections in the general population are reviewed here, along with the practical challenges to implementing these processes at scale in pediatric and adult SOTR, and their household members. The resources and logistics, including transplant-specific analyses pipelines to account for confounders such as polypharmacy and comorbidities, required in studies of pediatric and adult SOTR for the robust early detection of SARS-CoV-2, and other infections are also reviewed.


Subject(s)
COVID-19 , Organ Transplantation , Wearable Electronic Devices , Adult , Child , Humans , Pandemics , SARS-CoV-2
18.
Preprint in English | medRxiv | ID: ppmedrxiv-21253227

ABSTRACT

BackgroundTesting programs have been utilized as part of SARS-CoV-2 mitigation strategies on university campuses, and it is not known which strategies successfully identify cases and contain outbreaks. ObjectiveEvaluation of a testing program to control SARS-CoV-2 transmission at a large university. DesignProspective longitudinal study using remote contactless enrollment, daily mobile symptom and exposure tracking, and self-swab sample collection. Individuals were tested if the participant was (1) exposed to a known case, developed new symptoms, or reported high-risk behavior, (2) a member of a group experiencing an outbreak, or (3) at baseline upon enrollment. SettingAn urban, public university during Autumn quarter of 2020 ParticipantsStudents, staff, and faculty. MeasurementsSARS-CoV-2 PCR testing was conducted, and viral genome sequencing was performed. ResultsWe enrolled 16,476 individuals, performed 29,783 SARS-CoV-2 tests, and detected 236 infections. Greek community affiliation was the strongest risk factor for testing positive. 75.0% of positive cases reported at least one of the following: symptoms (60.8%), exposure (34.7%), or high-risk behaviors (21.5%). 88.1% of viral genomes (52/59) sequenced from Greek-affiliated students were genetically identical to at least one other genome detected, indicative of rapid SARS-CoV-2 spread within this group, compared to 37.9% (11/29) of genomes from non-Greek students and employees. LimitationsObservational study. ConclusionIn a setting of limited resources during a pandemic, we prioritized testing of individuals with symptoms and high-risk exposure during outbreaks. Rapid spread of SARS- CoV-2 occurred within outbreaks without evidence of further spread to the surrounding community. A testing program focused on high-risk populations may be effective as part of a comprehensive university-wide mitigation strategy to control the SARS-CoV-2 pandemic.

19.
J Digit Imaging ; 34(2): 290-296, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1092057

ABSTRACT

Disasters cause a major disruption to normal operations. Hospital information systems are often well-prepared for events such as fires or natural disasters. This type of disaster planning focuses on redundancy and manual workarounds. The SARS-CoV-2/COVID pandemic represented a new type of disaster for our radiology informatics team. In this pandemic, the information systems continued to work but the employees, and the computers that they worked with, had to be distanced. The purpose of this manuscript is to discuss the four phases of the disaster planning process: mitigation, planning, response, and recovery. We will illustrate the process with the example of how our radiology informatics team responded to the SARS-CoV-2/COVID pandemic.


Subject(s)
COVID-19 , Disaster Planning , Radiology , Humans , Informatics , SARS-CoV-2
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