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Background: SARS CoV 2 infection alters the immunological profiles of natural killer (NK) cells. However, whether NK anti-viral functions (direct cytotoxicity and/or antibody-dependent cell cytotoxicity (ADCC)) are impaired during severe COVID-19 and what host factors modulate these functions remain unclear. Method(s): Using functional assays, we examined the ability of NK cells from SARS-CoV-2 negative controls (n=12), mild COVID-19 patients (n=26), and hospitalized COVID-19 patients (n=41) to elicit direct cytotoxicity and ADCC [NK degranulation by flow] against cells expressing SARS-CoV-2 antigens. SARS-CoV- 2 N antigen plasma load was measured using an ultra-sensitive Simoa assay. We also phenotypically characterized the baseline expression of NK activating (CD16 and NKG2C), maturation (CD57), and inhibitory (NKG2A and the glyco-immune negative checkpoint Siglec-9) by flow cytometry. Finally, an anti-Siglec-9 blocking antibody was used to examine the impact of Siglec-9 expression on anti-SARS-CoV-2-specific ADCC [degranulation and target cell lysis]. Result(s): NK cells from hospitalized COVID-19 patients degranulate less against SARS-CoV-2-antigen-expressing cells (in direct cytolytic and ADCC assays) than did cells from mild COVID-19 patients or negative controls (Fig. 1A). The lower NK degranulation was associated with higher plasma levels of SARS-CoV-2 N-antigen (P<=0.02). Phenotypic and functional analyses showed that NK cells expressing Siglec-9 elicited higher ADCC than Siglec-9- NK cells (P<0.05;Fig. 1B). Consistently, Siglec-9+ NK cells expressed an activated and mature phenotype with higher expression of CD16, CD57, and NKG2C, and lower expression of NKG2A, than Siglec-9- NK cells (P<=0.03). These data are consistent with the concept that the NK cell subpopulation expressing Siglec-9 is highly activated and cytotoxic. However, the Siglec-9 molecule itself is an inhibitory receptor that restrains NK cytotoxicity during cancer and other infections. Indeed, blocking Siglec-9 significantly enhanced the ADCC-mediated NK degranulation and lysis of SARS-CoV-2-antigen-positive target cells (P<=0.05;Fig. 1C). Conclusion(s): These data support a model (Fig. 1D) in which the Siglec-9+ CD56dim NK subpopulation is cytotoxic even while being restrained by the inhibitory effects of Siglec-9. However, alleviating the Siglec-9-mediated restriction on NK cytotoxicity can further improve NK immune surveillance and presents an opportunity to develop novel immunotherapeutic tools against SARS-CoV-2 infected cells. (Figure Presented).
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It is well known that the COVID-19 pandemic caused significant treatment delays for dermatology patients, and recent studies demonstrate poor outcomes for patients with cutaneous T-cell lymphoma (CTCL) during this time. However, not much is known about patient reported delays in management of this condition following the pandemic. This study sought to evaluate patient-reported illness anxiety and delays in management of CTCL. Fifty-two CTCL patients were recruited from clinic from October 2020 to October 2021. Patients were asked to complete a 22-question survey adapted from the United States Census Household Pulse Survey. Control data was extrapolated from published national data from the Household Pulse Survey. Of 52 patients surveyed, 28 were male (59.6%). 25 identified as white (54.3%), 18 as Black (39.1%), 8 as Asian (15.3%) and 1 as Native American (2.2%). Average age was 57 years, age range 24-89 years. Results demonstrate that 32.6% (n=15) of respondents had a household member experience loss of employment since March 2020 compared to 39.6% of the US population. 46.8% of respondents vs. 32.3% US population noted some level of difficulty in paying for household expenses including medical care. Only 4.3% of respondents noted that they delayed receiving medical care due to the coronavirus pandemic. When compared to the US population (59.8%), a lower proportion of respondents (48.9%) noted symptoms of nervousness or anxiety over the past week. 27.7% of respondents vs. 46.1% of US population reported feelings of hopelessness or depression over the past week. These results demonstrate a low number of patients reporting care delays, possible due to the interval when data was collected, several months after COVID-19 onset. It is also possible that telehealth contributed to lessening delays in care. Overall, the results of this study reinforce the significant physical, financial, and emotional impact of CTCL on the daily lives of patients, and the heightened impact of COVID-19 on this population.Copyright © 2023
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Background: Maintenance dialysis patients' SARS-CoV-2 receptor binding spike antibody (RBD s-Ab) levels decline rapidly in the months following initial vaccination. We describe the association of RBD s-Ab levels with a subsequent diagnosis of COVID-19 and COVID-related hospitalization or death. Method(s): We identified all vaccinated adult maintenance dialysis patients at Dialysis Clinic, Inc. who were diagnosed with COVID-19 between June 20, 2021 and May 8, 2022. Descriptive analyses illustrate the association of RBD s-Ab levels assessed 7-45 days prior to COVID-19 diagnosis with COVID-related hospitalization or death. Result(s): There were 340 maintenance dialysis patients with RBD s-Ab levels assessed at a median 23 [16,40] days prior to COVID diagnosis, with mean age 65+/-13 years, 51% female, 51% White, 91% HD and vintage 4.3+/-4.3 years. While COVID-19 diagnosis and COVID-related hospitalization or death events occurred across RBD s-Ab levels (Figure), 74 of 93 (80%) COVID-related hospitalizations and 24 of 25 deaths (96%) occurred at RBD s-Ab level <500 BAU/mL Conclusion(s): Maintenance dialysis patients are at risk for serious COVID events when RBD s-Ab < 500 BAU/mL. Routine RBD s-Ab measurement informing personalized vaccination strategies to keep titers above 500 BAU/mL may benefit this high-risk population.
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Background: Preventing COVID-19 infection or its consequences through SARSCoV- 2 vaccination in maintenance dialysis patients, a high risk population, is imperative. We determined relative vaccine effectiveness (VE) of 1, 2, or 3 doses of an mRNA vaccine in preventing SARS-CoV-2 infection, hospitalization, and death. Method(s): All adult maintenance dialysis patients at Dialysis Clinic, Inc. offered an mRNA vaccine between 12/15/20 and 2/28/22 were included, with follow up time through 3/31/22. Using a multivariable logistic regression model, we calculated adjusted odds ratios (OR) for COVID-19 infection and associated hospitalization and death within 30 days during pre-Delta (12/15/20-6/19/21), Delta (6/20-12/18/21) and Omicron (12/19/21-2/28/22) periods. VE was calculated as (1-adjusted OR) x 100%. Patients were censored at infection, death, or transplantation. Result(s): The 17,309 maintenance dialysis patients included had mean age of 63+/-15 years, 58% male, 35% Black, 47% White, 87% HD and mean vintage 42+/-55 months. Across all three COVID-19 variant periods, VE increased with each successive mRNA dose received, improving protection against infection, hospitalization and death (Table). VE was highest among patients vaccinated with homologous mRNA-1273 regimens. Conclusion(s): Two or more SARS-CoV-2 mRNA vaccine doses exhibited VE protecting against COVID-19 related associated hospitalization and death in maintenance dialysis patients irrespective of variant era. At least 3 doses maximizes protection and may be necessary due to uremia-related mild to moderate immunodeficiency. (Table Presented).
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Background: Among patients receiving maintenance dialysis, seroresponse to an initial vaccine series wanes over time. Previously, we showed that additional doses elicit a substantial short-term increase in seroresponse. Here, we assess seroresponse over time in a national sample of maintenance dialysis patients. Method(s): Using retrospective clinical data, we assessed seroresponse to additional SARS-CoV-2 vaccine doses over time among maintenance dialysis patients cared for at Dialysis Clinic, Inc (DCI) facilities. Via a clinical protocol available to dialysis providers, antibodies against SARS-CoV-2 spike antigen were assessed monthly alongside routine labwork. Patients with history of COVID-19 prior to additional dose and patients who received Janssen vaccine as an additional dose were excluded. Titers after a second additional dose (i.e., for most, a fourth dose) or after COVID-19 diagnosis were excluded from analysis. Result(s): Among 1707 patients who had received an additional vaccine dose and had at least one titer level measured after the additional dose, more than 75% had a titer level at the upper limit of the assay in the first month after the additional dose. Titer levels then waned across vaccine types. By Month 6, median [IQR] titer was 68.37 [22.30, >=100] among Moderna recipients, 59.94 [39.90, 79.97] among Moderna half-dose recipients, and 71.29 [22.46, >=100] among Pfizer recipients. Conclusion(s): Among patients receiving maintenance dialysis, anti-spike IgG levels after an additional SARS-CoV-2 vaccine dose wane over time across vaccine types. These results suggest a role for routine antibody monitoring to assess possible need for further re-dosing.
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Background: Rapid and large-scale deployment of COVID-19 mRNA vaccines highlights the potential utility of developing nucleic acid vaccines (such as RNA and DNA vaccines) against infectious diseases, including HIV-1. However, as compared to SARS-CoV-2, HIV-1 pose some unique challenges-induction of neutralizing antibodies (NAbs) against HIV-1 (frequently a correlate of protection) requires presentation of trimeric and highly conformational epitopes to the immune system, and whether nucleic acid vaccines can enable direct in vivo production of antigens that retain critical antigenic profile has not yet been elucidated. Additionally, it was previously reported that Tier 2 NAbs cannot be induced in mice due to a lack of antibody repertoire, and vaccine studies were suggested to be performed in larger mammals such as rabbits/NHPs, inadvertently slowing down and increasing the costs of preclinical HIV-1 vaccine studies. Methods: In our study, we used the Antigen Conformation Tracing In Vivo by ELISA (ACTIVE) assay developed in house to characterize antigenic profiles of vaccines produced in vivo (from transfected muscle tissues). We analyzed induced cellular responses, using stimulation with overlapping peptides followed by intracellular cytokine staining and IFN-g ELIspot assays. We analyzed induced humoral responses by using both binding ELISA assays and TZM-BL based neutralizing assays, and attempted to map induced NAb epitopes by engineering selectively mutated pseudovirus. We performed antigen-specific B-cell sorting, and used the 10x genomics pipeline to characterize antibody sequences of proliferating B-cell clones. Results: We confirmed that in vivo produced vaccines retained key trimeric conformational epitopes and glycan profiles. Compared to protein vaccination, DNA vaccination uniquely and strongly induced both TFH, CD4+, CD8+ T-cell responses, and Tier 2 NAbs mapped to a previously unreported Env C3/V5 epitope. 5 unique NAbs were isolated, and confirmed to bind to the epitope using a Cryo-EM structure of NAb-MD39 complex at 3.8Å resolution. Conclusion: Our study confirmed that with appropriate vaccine delivery technology, murine models can be appropriately used for HIV-1 vaccine studies aimed at generating NAb responses. In addition, beyond potential functional immunity gains, DNA vaccines permit in vivo folding of structured antigens and provide significant cost and speed advantages for enabling rapid evaluation of new HIV vaccines.
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Background. DNA vaccines are safe, tolerable, elicit humoral and cellular responses, allow for repeated dosing over time, are thermostable at room temperature, and are easy to manufacture. We present a compilation of Phase 1 and Phase 2 data of Inovio's US COVID-19 DNA Vaccine (INO-4800) targeting the full-length Spike antigen of SARS-CoV-2. A South Korean Phase 2 study is ongoing. Methods. Participants in the open-label Phase 1 trial received 0.5 mg, 1.0 mg or 2.0 mg intradermally (ID) followed by electroporation (EP) at Days 0 and 28. An optional booster dose was administered >6 months post-dose 2. The Phase 2 further compared the 1.0 mg and 2.0 mg doses against placebo in a total of 401 participants randomized at a 3:3:1:1 ratio. ClinicalTrials.gov identifiers: NCT04336410 and NCT04642638 Results. The majority of adverse events (AEs) related to INO-4800 across both trials were mild in severity and did not increase in frequency with age and subsequent doses. In Phase 1, 78% (14/18) and 84% (16/19) of subjects generated neutralizing antibody responses with geometric mean titers (GMTs) of 17.4 (95%CI 8.3, 36.5) and 62.3 (95% CI 36.4, 106.7) in the 1.0 and 2.0 groups, respectively (Figure 1). By week 8, 74% (14/19) and 100% (19/19) subjects generated T cell responses by Th1- associated IFNγ ELISPOT assay . Following a booster dose, neutralizing GMTs rose to 82.2 (95% CI 38.2, 176.9) and 124.7 (95% CI 62.8, 247.7) in the 1.0 mg and 2.0 mg groups, respectively, demonstrating the ability of INO-4800 to boost (Figure 2). In Phase 2, neutralizing antibody responses demonstrated GMTs of 93.6 (95%CI 77.3, 113.4) in the 1.0 mg dose group and 150.6 (95%CI 123.8, 183.1) in the 2.0 mg dose group (Figure 3). Conclusion. INO-4800 appears safe and tolerable as a primary series and as a booster with the induction of both humoral and cellular immune responses. In addition to eliciting neutralizing antibodies, INO-4800 also induced T cell immune responses as demonstrated by IFNγ ELISpot. Finally, as a homologous booster, INO-4800, when administered 6-10.5 months following the primary series, resulted in an increased immune response without increase in reactogenicity. The 2.0 mg dose was selected for Phase 3 evaluation.
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Background. Global surveillance has identified emerging SARS-CoV-2 variants of concern (VOC) associated with increased transmissibility, disease severity, and resistance to neutralization by current vaccines under emergency use authorization (EUA). Here we assessed cross-immune responses of INO-4800 vaccinated subjects against SARS-CoV-2 VOCs. Methods. We used a SARS-CoV-2 IgG ELISA and a pseudo neutralization assay to assess humoral responses, and an IFNγ ELISpot to measure cellular responses against SARS-CoV-2 VOC in subjects immunized with the DNA vaccine, INO-4800. Results. IgG binding titers were not impacted between wild-type (WT) and B.1.1.7 or B.1.351 variants. An average 1.9-fold reduction was observed for the P.1 variant in subjects tested at week 8 after receiving two doses of INO-4800 (Figure 1a). We performed a SARS-CoV-2 pseudovirus neutralization assay using sera collected from 13 subjects two weeks after administration of a third dose of either 0.5 mg, 1 mg, or 2 mg of INO-4800. Neutralization was detected against WT and the emerging variants in all samples tested. The mean ID50 titers for the WT, B.1.1.7, B.1.351 and P.1. were 643 (range: 70-729), 295 (range: 46-886), 105 (range: 25-309), and 664 (range: 25-2087), respectively. Compared to WT, there was a 2.1 and 6.9-fold reduction for B.1.1.7 and B.1.351, respectively, while there was no difference between WT and the P.1 variant (Figure 1b). Next, we compared cellular immune responses to WT and SARS-CoV-2 Spike variants elicited by INO-4800 vaccination. We observed similar cellular responses to WT (median = 82.2 IQR = 58.9-205.3), B.1.1.7 (79.4, IQR = 38.9- 179.7), B.1.351 (80, IQR = 40.0-208.6) and P.1 (78.3, IQR = 53.1-177.8) Spike peptides (Figure 2). Conclusion. INO-4800 vaccination induced neutralizing antibodies against all variants tested, with reduced levels detected against B.1.351. IFNγ T cell responses were fully maintained against all variants tested.
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Background. First-generation COVID-19 vaccines are matched to spike protein of the Wuhan-H1 (WT) strain. Convalescent and vaccinee samples show reduced neutralization of SARS-CoV-2 variants of concern (VOC). Next generation DNA vaccines could be matched to single variants or synthetically designed for broader coverage of multiple VOCs. Methods. The synthetic consensus (SynCon®) sequence for INO-4802 SARSCoV-2 spike with focused RBD changes and dual proline mutations was codon-optimized (Figure 1). Sequences for wild-type (pWT) and B.1.351 (pB.1.351) were similarly optimized. Immunogenicity was evaluated in BALB/c mice. Pre-clinical efficacy was assessed in the Syrian Hamster model. Figure 1. Design Strategy for INO-4802 Results. INO-4802 induced potent neutralizing antibody responses against WT, B.1.1.7, P.1, and B.1.351 VOC in a murine model. pWT vaccinated animals showed a 3-fold reduction in mean neutralizing ID50 for the B.1.351 pseudotyped virus. INO-4802 immunized animals had significantly higher (p = 0.0408) neutralizing capacity (mean ID50 816.16). ID50 of pB.1.351 serum was reduced 7-fold for B.1.1.7 and significantly lower (p = 0.0068) than INO-4802 (317.44). INO-4802 neutralized WT (548.28) comparable to pWT. INO-4802 also neutralized P.1 (1026.6) (Figure 2). pWT, pB.1.351 or INO-4802 induced similar T-cell responses against all variants. INO-4802 skewed towards a TH1-response. All hamsters vaccinated with INO-4802 or pB.1.351 were protected from weight loss after B.1.351 live virus challenge. 4/6 pWT immunized hamsters were completely protected. pWT immunized hamsters neutralized WT (1090) but not B.1.351 (39.16). INO-4802 neutralized both WT (672.2) and B.1.351 (1121) (Figure 3). We observed higher increase of binding titers following heterologous boost with INO-4802 (3.6 - 4.4 log2-fold change) than homologous boost with pWT (2.0 - 2.4 log2 fold change) (Figure 4). Conclusion. Vaccines matching single VOCs, like pB.1.351 and pWT, elicit responses against the matched antigen but have reduced cross-reactivity. Presenting a pan-SARS-CoV-2 approach, INO-4802 may offer substantial advantages in terms of cross-strain protection, reduced susceptibility to escape mutants and non-restricted geographical use.
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Background: Older adults faced treatment decisions for kidney failure during the COVID-pandemic, despite high risk of hospitalization, intensive care, and death. Given heightened uncertainty, clinicians needed to adapt communication about risks, benefits, and treatment decisions during the COVID-19 pandemic. Understanding how to support decision-making during uncertain times can guide clinicians in future public health crises. Methods: Qualitative study using semi-structured interviews (August-December 2020) with CKD stage 4-5 patients, age 70+, carepartners, and clinicians in Boston, Portland, Maine, San Diego, and Chicago. Thematic analyses were conducted. Results: Among 76 participants (39 patients, 17 carepartners, 20 clinicians) 13 patients (33%) identified as Black, and 7 (18%) were receiving dialysis. Four themes characterized treatment decision-making during the COVID-19 pandemic: Difficulty communicatng risk: balancing hope with caution;Clinicians' increased support for home dialysis;Patient confidence in chosen modality;and Coping with uncertainty and isolation in CKD. Clinicians struggled to balance discussion of COVID-19 risks while preserving hope. Black patients reported fewer conversations about COVID-19 risks than White patients and had more unaddressed questions. Clinicians reported being more open to home dialysis than pre-COVID-19. While some patients expressed interested in conservative management, few clinicians offered conservative management as an option. All patients who had initiated treatment prior to COVID-19, irrespective of modality, believed that their treatment was safest and optimal during the pandemic. With few clinical converations incorporating COVID-19-specific risks, patients and carepartners struggled to cope, finding both in-person and telehealth visits safe but isolating. Conclusions: Although clinicians struggled communicating about COVID-19 leaving patients with unadressed concerns, patients across modalities felt safe and confident in their treatment. Clinicians developed an openness to home dialysis, though few offered conservative management despite patient preferences. Research should examine optimal approaches to enhance communication and shared-decision making to prepare for future systemic challenges.
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Background: Durability of SARS-CoV-2 receptor-binding domain spike antibody (RBD s-Ab) levels among patients receiving dialysis after COVID-19 [WDE1] is unknown[EL2] beyond 6 months. We describe the persistence (index value ≥ 1 and ≥ 2 U/L) of semi-quantitative RBD s-Ab levels in dialysis patients over 14 month period. Methods: All maintenance dialysis patients (≥18 years old) within Dialysis Clinic, Inc. 260 clinics in 28 states with COVID-19 infection history and RBD s-Ab levels determined between Jan 1 and May 23, 2021 were included. On the day of RBD s-Ab level determination, patient demographics (age, sex, race, modality, ESKD vintage) and days since COVID-19 diagnosis were determined. Patient RBD s-Ab levels obtained after COVID-19 vaccination were excluded. Results: A total of 515 patients, mean age 62±14 years, 57% male, 46% White, 94% HD and vintage 4.6±4.4 years[EL1], [HJM2] had 835 RBD s-Ab levels assessed at a median of 59 days (range 0-422 days) post COVID-19 diagnosis. RBD s-Ab levels were assessed 1, 2 or ≥3 times in 64%, 18% and 18% patients, respectively. Only 32 (6.2%) patients had undetectable RBD s-Ab on the last draw. A cross sectional summary of the last available RBD s-Ab levels suggests that titers remain detectable for long duration (Figure[EL3] [HJM4]). In patients (N=186;36%) with multiple RBD s-Ab levels (mean 28±15;median 28 days between levels), subsequent values were higher, lower [EL5] [HJM6] or unchanged 7%, 16% and 77% of time[EL7], respectively. Conclusions: Most maintenance dialysis patients sampled developed SARS-CoV-2 RBD s-Ab after COVID diagnosis, and durability extends up to 14 months. Further elucidation of longitudinal RBD s-Ab values post-COVID-19 infection as well as after completing vaccination for SARS-CoV-2 is needed.
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Background: Vaccines against SARS-CoV-2 are highly effective in the general population;however, their efficacy may be diminished in maintenance dialysis patients, a population particularly vulnerable to COVID-19. We assessed vaccine response in a national sample of maintenance dialysis patients. Methods: Using retrospective clinical data, we assessed seroresponse to vaccine among maintenance dialysis patients cared for at 130 Dialysis Clinic, Inc (DCI) facilities. Via a clinical protocol available to early vaccinating facilities, antibodies against SARSCoV-2 spike antigen were semi-quantitatively assessed beginning with the monthly blood draw at least two weeks after completion of a SARS-CoV-2 vaccine series. Vaccine response was defined as a titer ≥2 U/L, and logistic regression analysis was used to identify characteristics associated with response. Patients with history of COVID-19 prior to antibody assessment were excluded. Results: Among 1,352 patients, 996 (74%) had a serologic response. Serologic response differed significantly by vaccine type: 314/386 (81%) among BNT162b2/ Pfizer recipients, 615/655 (94%) among mRNA-1273/Moderna recipients, and 67/311 (22%) among Ad26.COV2.S/Janssen recipients. Age greater than 75, lack of hepatitis B immunity, immune-modulating medication, lower serum albumin, and COPD were associated with vaccine non-response (Figure). Conclusions: Serologic response to mRNA vaccines is robust among chronic dialysis patients, and the use of mRNA vaccines should be promoted aggressively in this vulnerable population. High rates of non-response to the Janssen vaccine warrant further study. Future research should evaluate the potential role for boosters and whether seroresponse corresponds with protection from COVID-19.
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Background: Acute kidney injury (AKI) requiring kidney replacement therapy (KRT) occurs in as many as one in five critically ill patients with COVID-19. Expanding on previous work by this group, we examined the association of clinical factors at the time of KRT initiation with the outcome of kidney recovery at hospital discharge, accounting for the competing outcome of death. Methods: We used data from the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID), a multicenter cohort study that enrolled adults with COVID-19 admitted to ICUs at 68 hospitals across the US from March 4 to June 22, 2020. Among those who acutely required KRT, the outcome of kidney non-recovery (continued dialysis dependence at hospital discharge) was explored with multinomial logistic regression, with kidney recovery (independence from dialysis at discharge) as the reference outcome and death as an alternate outcome. Exposures of interest included demographics, baseline medical status, and markers of illness acuity at the time of KRT initiation. Results: Of 876 patients with AKI-KRT, 588 (67%) died, 95 (11%) survived to discharge and remained dependent on KRT, and 193 (22%) survived to discharge without KRT dependence. Patients with lower baseline eGFR had greater odds of kidney non-recovery, with OR 8.58 (95% CI: 3.03-24.28) among patients with eGFR ≤15 vs >60. Reduced urine output on the day of KRT initiation was also associated with kidney non-recovery, with OR 4.23 (95% CI: 1.61-11.15) for urine output <50 mL/day vs >500 mL/day (Figure). Conclusions: Among critically ill patients with COVID-19 with AKI requiring KRT, lower baseline kidney function and reduced urine output at the time of KRT initiation are associated with kidney non-recovery.
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Background: Novel coronaviruses (CoV) caused 3 global outbreaks over the past 2 decades: SARS-CoV (2002), MERS-CoV (2012), and 2019-nCoV in Wuhan, China. Each caused pneumonia with mortality of 10%, 35% and 2%, respectively (2019-nCoV estimated). GLS-5300 DNA vaccine targeting MERS-CoV Spike (S) was first to enter clinical trial, was safe and immunogenic (Lancet ID;2019). In Phase I, a 3 dose series at Day0, 4 and 12 weeks of GLS-5300 at either 0.67, 2 or 6mg was given IM followed by electroporation (EP, IM+EP) with CELLECTRA-5P device. GLS-5300 induced antibodies (Abs) in 94%, Tcell response in 76%, and neutralizing Abs in 50% of participants. No dose response was observed. GLS-5300 response was similar to those recovered from natural MERS-CoV infection. The absence of dose response and prior experience showing benefits of ID+EP vs IM+EP (JID;2019) led us to design this trial of lower ID dosing with an arm for a 2-dose regimen. We report results from MERS-002, the ongoing Phase I/IIa study of GLS-5300. Methods: MERS-002 is an open label, dose ranging, phase I/IIa study of GLS-5300. Participants were enrolled at 2 Korean sites into 3 groups receiving GLS-5300 ID+EP with the CELLECTRA-3P device: Group 1 received three 0.3mg doses at Day0 and weeks 4 and 12;Group 2 received three 0.6mg doses at Day0 and weeks 4 and 12;Group 3 received two 0.6mg doses at Day0 and week 8. Safety and tolerability of GLS-5300 was evaluated at each visit. Samples were collected at baseline, before each dose, and at both 2 and 4 weeks post dose 2 and post dose 3. Study data through 4 weeks after the primary series for a subset of immunoassays were included here. Findings: GLS-5300 given ID+EP was well-tolerated with no vaccine-associated SAEs. Preliminary results were available for: full length S (flS) ELISA, EMC2012-Vero neutralization (MERS-neut) and MERS-CoV S IFNg ELISPOT. GLS-5300 at 0.6mg induced MERS-CoV-specific Abs by flS ELISA and MERS-neut in 74% and 48%, respectively, after 1 dose. After the 2 or 3 dose vaccine series at 0.6mg per dose, flS ELISA response was seen in 100% and 92% of participants, respectively. MERS-neut response was 92% in both 2 and 3 dose 0.6mg groups. Antibody responses and rates were higher during and after primary series in 0.6mg group regardless of regimen than 0.3mg per dose. GLS-5300 induced Tcell responses via MERS-CoV IFNg ELISPOT in 60% and 84% receiving 0.6mg after the 2 or 3 dose series, respectively. Compared to 0.67mg of GLS-5300 given IM+EP in the first trial, 0.6mg of GLS-5300 given ID+EP in MERS-002, binding Abs appeared sooner and neutralizing Abs were observed in a higher fraction of participants (92% vs 50%) while Tcell reactivity was similar between vaccination schema. Conclusions: GLS-5300 was well tolerated with no vaccine-associated SAEs. Like prior studies, DNA vaccines given by ID+EP had fewer injection-related AEs relative to IM+EP. In MERS-002, 0.6mg of GLS-5300 in a 2-dose regimen spanning 8 weeks had similar reactivity and rate to the longer 3-dose regimen. GLS-5300 was safe and immunogenic when given IM+EP and, similarly, when given ID+EP in both 2- and 3-dose regimens in this ongoing MERS-002 Phase I/IIa trial. A Phase II clinical evaluation of the use of GLS-5300 to prevent MERS-CoV infection in endemic regions is planned.