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1.
Cancer Research ; 82(12), 2022.
Article in English | EMBASE | ID: covidwho-1986491

ABSTRACT

The immunogenicity and efficacy of RNA-based vaccine platforms has been abundantly shown through their application in prophylactic SARS-CoV2 vaccines. Contrasting to mRNA based vectors, self amplifying mRNA platforms may offer dose-sparing and superior induction of T cell responses, and may also trigger distinct innate immune pathways, which may exert adjuvanting or inhibiting effects on vaccine-induced immunity. Optimal dosing for a novel self-amplifying mRNA (SAM) in a heterologous prime-boost vaccination approach consisting of Chimpanzee Adenovirus (ChAd) prime and SAM boosts was evaluated in two first-in-human phase 1/2 clinical trials assessing personalized neoantigen vaccines in patients with metastatic cancer (NCT03639714, NCT03953235). SAM vaccine dose escalation was performed to assess safety, tolerability, and immunogenicity, including administration of up to 8 SAM doses at 30, 100, or 300μg following a fixed dose of ChAd (1012 vp) over the course of a year. SAM was safe and well tolerated at all 3 dose levels, with no evidence of increasing reactogenicity with sequential doses. However, while immune monitoring via IFNγ ELISpot revealed that the 30μg SAM dose boosted T cell responses induced by the ChAd prime, the 100μg and 300μg SAM doses resulted in maintenance of T cell levels, without a clear T cell boost, suggesting a non-linear and likely bell-shaped dose-response curve to SAM in humans. Follow-up studies in non-human primates (NHPs) using a model antigen revealed dose-dependent increases in serum IFNa levels following administration of increasing SAM doses. Similarly, while multiple inflammatory cytokines were transiently increased following both ChAd and SAM administration in patients, serum IFNa levels were only increased 24h post SAM administration and correlated positively with SAM dose. Increased IFNa levels post SAM dosing suggested activation of mRNA-sensing innate immune pathways that may reduce the amplification of, and/or antigen expression by, the SAM vector and thus blunt T cell boosting at higher SAM doses. In addition, analysis of T cell responses in patients and NHPs showed increased boosting of T cell responses with longer intervals. These data lead to a reduction of the SAM dose to 30μg and adjusting SAM dosing intervals to 8 weeks in the Phase 2 portion of these clinical studies. Multiple patients have been dosed with the adjusted vaccine regimen, and preliminary data suggest robust boosting of ChAd-induced neoantigen-specific T cell responses with the selected SAM dosing regimen and the 30μg dose. We anticipate that this translational approach of adjusting clinical vaccine regimens based on strong translational immune data will increase the potency of our heterologous neoantigen vaccine, and subsequently provide more durable clinical benefit to patients with cancer.

2.
Gastroenterology ; 162(7):S-593, 2022.
Article in English | EMBASE | ID: covidwho-1967335

ABSTRACT

Background: Several SARS-CoV-2 vaccines are highly effective in preventing most infections, serious disease, hospitalization, and death from COVID-19 in the general population, but data regarding their use and efficacy in patients with inflammatory bowel disease (IBD) are limited. In this study we assessed the use patterns and efficacy of SARS-CoV-2 vaccines in patients with IBD. Methods: We established a multicenter matched case-control cohort of patients with IBD [Crohn's disease (CD), ulcerative colitis (UC)] and COVID-19 between February 2020 and December 2020 for the Surveillance of COVID-19 Impact on Long- Term Outcomes in IBD (SCOUT IBD) study. Cases were defined by the presence of COVID- 19-related symptoms and confirmatory SARS-CoV-2 PCR or IgG testing and non-COVID controls were defined as absence of symptoms and both a negative PCR and IgG in 2020. Cases were matched 1:1 to controls based on age, sex and IBD type. Data were collected on vaccine administration in 2021 and incidence of interval COVID-19 (defined as above) between January and September 2021. Results: The total cohort included 502 patients with IBD [UC (n=222, 44%), CD (n=278, 55%), IBD-undefined (n=2, 1%)] of whom 251 had a history of COVID-19 in 2020. The overall vaccination rate was 61% (n=306) with 189 (62%) patients receiving Pfizer-BioNTech, 101 (33%) Moderna, and 12 (4%) Johnson & Johnson. Vaccinated patients were more likely to be older (P=0.02), female (P=0.07), have a co-morbidity (cardiovascular, respiratory, renal) (P=0.04), or currently be on a biologic (P=0.01), and less likely to have had prior COVID-19 (P<0.001) than patients who did not get vaccinated (Table 1). The overall incidence of interval COVID-19 was 1.6% (N=8), with an infection rate of 0.3% (1/311) in vaccinated patients vs. 3.7% (7/184) in unvaccinated patients (P<0.01). Of infections occurring in unvaccinated patients, 1/7 (14.2%) was severe and required hospitalization requiring ICU admission, and the breakthrough infection in the vaccinated patient was mild and self-limited. COVID-19 reinfection occurred in one patient (0.4%) with prior COVID-19 who was unvaccinated. Under multivariable logistic regression, COVID-19 vaccination (aOR 0.05, 95% CI 0.01-0.41) and prior COVID-19 infection (OR 0.07, 95% CI 0.01-0.63) were highly protective against interval COVID-19. Conclusion: COVID-19 vaccines are effective in patients with IBD and markedly reduce the incidence of COVID-19. Prior COVID-19 is also protective against subsequent infection, although re-infections may occur at a very low rate. These results reaffirm the importance of COVID-19 vaccination in patients with IBD.(Table Presented)(Table Presented)

3.
Gastroenterology ; 162(7):S-592-S-593, 2022.
Article in English | EMBASE | ID: covidwho-1967334

ABSTRACT

Background: Inflammatory bowel disease (IBD) and IBD-related biologic therapies are not associated with worse outcomes of Coronavirus Disease 2019 (COVID-19), however, data are lacking regarding the long-term impact of COVID-19 and its inflammatory sequelae on the disease course of IBD. We aimed to investigate the long-term outcomes of patients with IBD and COVID-19. Methods: We performed a multicenter matched case-control study of patients with IBD [Crohn's disease (CD), ulcerative colitis (UC)] and COVID-19 between February 2020 and December 2020 at 5 large health systems. Cases were defined by the presence of COVID-19-related symptoms and confirmatory SARS-CoV-2 PCR or IgG testing. Non-COVID controls were defined as absence of symptoms and both a negative PCR and IgG during the study entry period. Cases were matched 1:1 to controls based on age, sex and IBD type. The primary composite outcome was IBD-related hospitalization or surgery, and outcomes were sub-stratified by COVID-19 severity. Results: We identified 251 cases with IBD [UC (n=111, 44%), CD (n=139, 55%)] and confirmed COVID-19, matched with 251 non-COVID-19 IBD controls, with a median follow-up of 394 days. COVID-19 patients had higher rates of prior IBD-related hospitalizations (36% vs. 27%;P=0.03), corticosteroid use (75% vs. 65%;P=0.06), and biologic exposure (73% vs. 64%;P=0.04) than controls. There were no differences in UC extent or CD phenotype between groups. In COVID-19 positive patients, the most common symptoms were fever (61%), cough (48%), fatigue (30%) and diarrhea (28%). Severe COVID-19 (defined as hospitalization, ICU requirement or mechanical ventilation) occurred in 16% (n=39) of cases. The primary composite outcome of IBD-related hospitalization or surgery occurred in 12% (n=38) of cases vs. 15% (n=29) of controls (P=0.24;Table 1). When further stratified by COVID-19 severity, the incidence of the primary composite outcome was highest in patients with severe COVID-19, followed by controls and non-severe COVID-19 (Figure 1). Under multivariate Cox regression, severe COVID-19 remained a predictor of worse IBD outcomes (aHR 2.09, 95% CI 0.91-4.86) whereas non-severe COVID-19 was associated with decreased risk (aHR 0.52, 95% CI 0.28- 0.99). Prior IBD-related hospitalization or surgery (aHR 3.10, 95% CI 1.70-6.57) and current steroid use (aHR 2.17, 95% CI 0.95-4.94) were also predictive of worse IBD outcomes. Conclusion: In this matched case-control study, a history of any COVID-19 infection did not appear to exacerbate the course of IBD, however, severe COVID-19 was associated with worse IBD outcomes. These data suggest that the inflammatory sequelae of COVID-19 may adversely impact the subsequent disease course of IBD. Further studies are required to confirm these associations, which underscore the importance of COVID-19 mitigation measures.(Table Presented) (Figure Presented)

4.
Journal of the American College of Cardiology ; 79(9):1088, 2022.
Article in English | EMBASE | ID: covidwho-1768626

ABSTRACT

Background Although the number of patients presenting with non-ST elevation myocardial infarction (NSTEMI) has drastically reduced in the coronavirus-19 pandemic era, increased mortality was reported. A plausible explanation for increased mortality was suggested as the delay of arrival at the hospital due to patients’ reticence of their symptoms. However, evidence to support the suggested explanation is lacking. Methods From the nationwide prospective registry, we evaluated 6,544 patients with NSTEMI. Study patients were categorized into two groups according to their symptom-to-door (StD) time (<24 h or ≥24 h). The primary outcome was 3-year all-cause mortality, and the secondary outcome was 3-year composite of all-cause mortality, recurrent MI, and hospitalization for heart failure. Results Overall, 27.9% patients were classified into the StD time ≥24 h group. The StD time ≥24 h group had higher all-cause mortality (17.0% vs. 10.5%, p<0.001) and incidence of secondary outcome (23.3% vs. 15.7%, p<0.001) than the StD time <24 h group. In the multivariable analysis, independent predictors of delayed arrival at the hospital were the elderly, female, non-specific symptoms such as atypical chest pain or dyspnea, diabetes, and no use of emergency medical services. Conclusion Delayed arrival (StD time ≥24 h) is associated with an increased risk of 3-year all-cause mortality and composite outcomes in patients with NSTEMI. [Formula presented]

5.
Journal of Virology ; 95(14):16, 2021.
Article in English | Web of Science | ID: covidwho-1486522

ABSTRACT

We describe a mammalian cell-based assay to identify coronavirus 3CL protease (3CLpro) inhibitors. This assay is based on rescuing protease-mediated cytotoxicity and does not require live virus. By enabling the facile testing of compounds across a range of 15 distantly related coronavirus 3CLpro enzymes, we identified compounds with broad 3CLpro-inhibitory activity. We also adapted the assay for use in compound screening and in doing so uncovered additional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CLpro inhibitors. We observed strong concordance between data emerging from this assay and those obtained from live virus testing. The reported approach democratizes the testing of 3CLpro inhibitors by developing a simplified method for identifying coronavirus 3CLpro inhibitors that can be used by the majority of laboratories, rather than the few with extensive biosafety infrastructure. We identified two lead compounds, GC376 and compound 4, with broad activity against all 3CL proteases tested, including 3CLpro enzymes from understudied zoonotic coronaviruses. IMPORTANCE Multiple coronavirus pandemics have occurred over the last 2 decades. This has highlighted a need to be proactive in the development of therapeutics that can be readily deployed in the case of future coronavirus pandemics. We developed and validated a simplified cell-based assay for the identification of chemical inhibitors of 3CL proteases encoded by a wide range of coronaviruses. This assay is reporter free, does not require specialized biocontainment, and is optimized for performance in high-throughput screening. By testing reported 3CL protease inhibitors against a large collection of 3CL proteases with variable sequence similarity, we identified compounds with broad activity against 3CL proteases and uncovered structural insights into features that contribute to their broad activity. Furthermore, we demonstrated that this assay is suitable for identifying chemical inhibitors of pro teases from families other than 3CL proteases.

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