Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

1935. COVID-19 mRNA Vaccination Reduces the Occurrence of Post-COVID Conditions in U.S. Children Aged 5-17 Years Following Omicron SARS-CoV-2 Infection, July 2021-September 2022

Abstract Background An estimated 1-3% of children with SARS-CoV-2 infection will develop Post-COVID Conditions (PCC). This study evaluates mRNA COVID-19 vaccine impact on likelihood of PCC in children. Methods A multi-site cohort of children enrolled 7/21/2021-9/1/2022 underwent weekly SARS-CoV-2 screening tests and were surveyed via self- or parental report 12/1/2022-5/31/2023 regarding PCC (defined as ≥1 new or on-going symptoms lasting ≥ 1 month after infection). Multivariable logistic regression was performed to estimate the occurrence of PCC by vaccination status among children aged 5–17 years whose first PCR-confirmed SARS-CoV-2 infection occurred in-study with Omicron variant, who completed the survey >60 days from infection, and who were vaccine age-eligible at time of infection per ACIP recommendations. Vaccination status was categorized as vaccinated (at least primary series completed >14 days before infection) and unvaccinated (no vaccine doses before infection). Vaccination status was verified through vaccine registry and/or medical records. Results Of 622 participants surveyed, 5% (n=28) had PCC (Table 1) and 67% (n=474) were vaccinated (Table 2). Surveys were completed a median (IQR) of 203.7 days (119.0–293.0) after infection. Children with non-Hispanic Black race/ethnicity and good/fair/poor self-rated baseline health were more likely to report PCC. Children aged 12-18 years, Non-Hispanic Asian and White children, those reporting symptomatic SARS-CoV-2 infection, and those with excellent/very good self-rated baseline health were more likely to report vaccination When comparing children with and without PCC symptoms, COVID-19 mRNA vaccination was associated with a decreased likelihood of >1 PCC symptom (aOR 0.66, 95% CI 0.43-0.99), >2 PCC symptoms (aOR 0.52, 95% 0.32-0.83), and respiratory PCC symptoms (aOR 0.53, 95% CI 0.33-0.87) (Table 3). Figure 1.Relative Risk of Post-COVID Conditions among Patients who Received Paxlovid, Ages ≥50 (N=564,303)Figure 2.Relative Risk of Post-COVID Conditions among Patients who Received Paxlovid, Ages 18-49 (N=292,818)Figure 3.Relative Risk of Post-COVID Conditions among Patients who Received Paxlovid, Ages 12-17 (N=17,178) Conclusion In this study, mRNA COVID-19 vaccination appeared to be protective against PCC in children following Omicron SARS-CoV-2 infection. The adjusted ORs correspond to an estimated 34%, 48%, and 47% reduced likelihood of >1, >2, and respiratory PCC symptoms among vaccinated children, respectively. These findings support COVID-19 vaccination for children and may encourage increased pediatric vaccine uptake. Disclosures Lisa Gwynn, MBA, MSPH, Merck: Honorari

2082. Effectiveness of Bivalent mRNA Vaccines in Preventing SARS-CoV-2 Infection Among Children Aged 5-17 years: an Evaluation of Multicenter Prospective Cohorts, United States, September 2022 - January 2023

Abstract Background The bivalent mRNA COVID-19 vaccine booster dose, composed of mRNA from ancestral and Omicron BA.4/BA.5 strains, was recommended for adolescents aged ≥12 years on September 1, 2022, and for children aged 5–11 years on October 12, 2022. However, data demonstrating the effectiveness of bivalent boosters among children and adolescents are limited. During Omicron variant sublineage predominance, September 4, 2022 – February 4, 2023, we conducted a multicenter prospective cohort study at 7 sites in the United States to assess vaccine effectiveness (VE) of bivalent COVID-19 vaccine boosters against laboratory-confirmed SARS-CoV-2 virus infection among children aged 5–17 years. Methods Participants collected weekly nasal swabs, irrespective of symptoms, and at onset of symptoms if present outside of their weekly swab cadence. Vaccination status was captured from periodic surveys (self-report), supplemented with queries from the state immunization information systems, and abstraction of electronic medical records system, when available. All respiratory swabs were tested for SARS-CoV-2 using reverse transcription-polymerase chain reaction. Symptomatic infection was defined as ≥2 COVID-like illness symptoms within 7 days of specimen collection. Cox proportional hazards models were used to estimate hazard ratios of infections comparing participants with receipt of a bivalent booster to participants without (either unvaccinated or received monovalent only), adjusting for age, sex, race/ethnicity, underlying health conditions, prior infection status, geographic site, and local virus prevalence. Results Among 3,331 participants aged 5-17 years, adjusted VE against infection was 51% (95% CI: 29–66%). When stratified by age, adjusted VE was 48% (95% CI: 15-68%) for 5-11 year old participants and 55% (95% CI: 17-76%) for 12-17 year old participants. Against symptomatic infection, adjusted VE among 5-17 year old participants was 51% (95% CI: 14-72%). Conclusion These results demonstrate that the COVID-19 bivalent booster reduces risk of SARS-CoV-2 infection and symptomatic illness among children and adolescents. All eligible children and adolescents should remain up to date with recommended COVID-19 vaccinations. Disclosures Helen Y. Chu, MD, MPH, Abbvie: Advisor/Consultant|Ellume: Advisor/Consultant|Ellume: Grant/Research Support|Merck: Advisor/Consultant|Pfizer: Advisor/Consultant|Vir: Advisor/Consultant Janet A. Englund, MD, Ark Biopharma: Advisor/Consultant|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Meissa Vaccines: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant Emily T. Martin, PhD, MPH, Merck: Grant/Research Support Arnold Monto, MD, Roche: Advisor/Consultant|Roche: Honorari

Detection and Stability of SARS-CoV-2 in Three Self-Collected Specimen Types: Flocked Midturbinate Swab (MTS) in Viral Transport Media, Foam MTS, and Saliva.

Respiratory specimen collection materials shortages hampers severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. We compared specimen alternatives and evaluated SARS-CoV-2 RNA stability under simulated shipping conditions. We compared concordance of RT-PCR detection of SARS-CoV-2 from flocked midturbinate swabs (MTS) in viral transport media (VTM), foam MTS without VTM, and saliva. Specimens were collected between August 2020 and April 2021 from three prospective cohorts. We compared RT-PCR cycle quantification (Cq) for Spike (S), Nucleocapsid (N), and the Open Reading Frame 1ab (ORF) genes for flocked MTS and saliva specimens tested before and after exposure to a range of storage temperatures (4-30°C) and times (2, 3, and 7 days). Of 1,900 illnesses with ≥2 specimen types tested, 335 (18%) had SARS-CoV-2 detected in ≥1 specimen; 304 (91%) were concordant across specimen types. Among illnesses with SARS-CoV-2 detection, 97% (95% confidence interval [CI]: 94-98%) were positive on flocked MTS, 99% (95% CI: 97-100%) on saliva, and 89% (95% CI: 84-93%) on foam MTS. SARS-CoV-2 RNA was detected in flocked MTS and saliva stored up to 30°C for 7 days. All specimen types provided highly concordant SARS-CoV-2 results. These findings support a range of viable options for specimen types, collection, and transport methods that may facilitate SARS-CoV-2 testing during supply and personnel shortages. IMPORTANCE Findings from this analysis indicate that (1) self-collection of flocked and foam MTS and saliva samples is feasible in both adults and children, (2) foam MTS with VTM and saliva are both viable and reasonable alternatives to traditional flocked MTS in VTM for SARS-CoV-2 detection, and (3) these sample types may be stored and transported at ambient temperatures for up to 7 days without compromising sample quality. These findings support methods of sample collection for SARS-CoV-2 detection that may facilitate widespread community testing in the setting of supply and personnel shortages during the current pandemic

Hybrid immunity and SARS-CoV-2 antibodies: results of the HEROES-RECOVER prospective cohort study

There are limited data on whether hybrid immunity differs by count and order of immunity-conferring events (SARS-CoV-2 infection or COVID-19 vaccination). From a cohort of health care personnel, first responders, and other frontline workers in six US states, we examined heterogeneity of the effect of hybrid immunity on SARS-CoV-2 antibody levels. Exposures included event-count (sum of infections and vaccine doses) and event-order, categorized into seven permutations of vaccination and/or infection. Outcome was level of serum binding antibodies against receptor binding domain (RBD) of the ancestral SARS-CoV-2 spike protein (total RBD-binding Ig), measured by enzyme-linked immunosorbent assay. Mean antibody levels were examined up to 365 days after each of the 1st-7th events. Analysis included 5,793 participants measured from August 7, 2020 to April 15, 2023. Hybrid immunity from infection before one or two vaccine doses elicited modestly superior antibody responses after the 2nd and 3rd events (compared to infections or vaccine-doses alone). This superiority was not evident after the 4th and 5th events (additional doses). Among adults infected before vaccination, adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated-only) were 1.23 (1.14-1.33), 1.09 (1.03-1.14), 0.87 (0.81-0.94), and 0.99 (0.85-1.15) after the 2nd-5th events, respectively. Post-vaccination infections elicited superior responses: adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated-only) were: 0.93 (0.75-1.17), 1.11 (1.06-1.16), 1.17 (1.11-1.24), and 1.20 (1.07-1.34) after the 2nd-5th events, respectively. Findings reflecting heterogeneity in antibody levels by permutations of infection and vaccination history could inform COVID-19 vaccination policy

Research on the Epidemiology of SARS-CoV-2 in Essential Response Personnel (RECOVER): Protocol for a Multisite Longitudinal Cohort Study (Preprint)

BACKGROUND Workers critical to emergency response and continuity of essential services during the COVID-19 pandemic are at a disproportionally high risk of SARS-CoV-2 infection. Prospective cohort studies are needed for enhancing the understanding of the incidence of symptomatic and asymptomatic SARS-CoV-2 infections, identifying risk factors, assessing clinical outcomes, and determining the effectiveness of vaccination. OBJECTIVE The Research on the Epidemiology of SARS-CoV-2 in Essential Response Personnel (RECOVER) prospective cohort study was designed to estimate the incidence of symptomatic and asymptomatic SARS-CoV-2 infections, examine the risk factors for infection and clinical spectrum of illness, and assess the effectiveness of vaccination among essential workers. METHODS The RECOVER multisite network was initiated in August 2020 and aims to enroll 3000 health care personnel (HCP), first responders, and other essential and frontline workers (EFWs) at 6 US locations. Data on participant demographics, medical history, and vaccination history are collected at baseline and throughout the study. Active surveillance for the symptoms of COVID-19–like illness (CLI), access of medical care, and symptom duration is performed by text messages, emails, and direct participant or medical record reports. Participants self-collect a mid-turbinate nasal swab weekly, regardless of symptoms, and 2 additional respiratory specimens at the onset of CLI. Blood is collected upon enrollment, every 3 months, approximately 28 days after a reverse transcription polymerase chain reaction (RT-PCR)–confirmed SARS-CoV-2 infection, and 14 to 28 days after a dose of any COVID-19 vaccine. From February 2021, household members of RT-PCR–confirmed participants are self-collecting mid-turbinate nasal swabs daily for 10 days. RESULTS The study observation period began in August 2020 and is expected to continue through spring 2022. There are 2623 actively enrolled RECOVER participants, including 280 participants who have been found to be positive for SARS-CoV-2 by RT-PCR. Enrollment is ongoing at 3 of the 6 study sites. CONCLUSIONS Data collected through the cohort are expected to provide important public health information for essential workers at high risk for occupational exposure to SARS-CoV-2 and allow early evaluation of COVID-19 vaccine effectiveness. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/31574 </sec

Effectiveness of Bivalent mRNA COVID-19 Vaccines in Preventing SARS-CoV-2 Infection in Children and Adolescents Aged 5 to 17 Years

Bivalent mRNA COVID-19 vaccines were recommended in the US for children and adolescents aged 12 years or older on September 1, 2022, and for children aged 5 to 11 years on October 12, 2022; however, data demonstrating the effectiveness of bivalent COVID-19 vaccines are limited. To assess the effectiveness of bivalent COVID-19 vaccines against SARS-CoV-2 infection and symptomatic COVID-19 among children and adolescents. Data for the period September 4, 2022, to January 31, 2023, were combined from 3 prospective US cohort studies (6 sites total) and used to estimate COVID-19 vaccine effectiveness among children and adolescents aged 5 to 17 years. A total of 2959 participants completed periodic surveys (demographics, household characteristics, chronic medical conditions, and COVID-19 symptoms) and submitted weekly self-collected nasal swabs (irrespective of symptoms); participants submitted additional nasal swabs at the onset of any symptoms. Vaccination status was captured from the periodic surveys and supplemented with data from state immunization information systems and electronic medical records. Respiratory swabs were tested for the presence of the SARS-CoV-2 virus using reverse transcriptase-polymerase chain reaction. SARS-CoV-2 infection was defined as a positive test regardless of symptoms. Symptomatic COVID-19 was defined as a positive test and 2 or more COVID-19 symptoms within 7 days of specimen collection. Cox proportional hazards models were used to estimate hazard ratios for SARS-CoV-2 infection and symptomatic COVID-19 among participants who received a bivalent COVID-19 vaccine dose vs participants who received no vaccine or monovalent vaccine doses only. Models were adjusted for age, sex, race, ethnicity, underlying health conditions, prior SARS-CoV-2 infection status, geographic site, proportion of circulating variants by site, and local virus prevalence. Of the 2959 participants (47.8% were female; median age, 10.6 years [IQR, 8.0-13.2 years]; 64.6% were non-Hispanic White) included in this analysis, 25.4% received a bivalent COVID-19 vaccine dose. During the study period, 426 participants (14.4%) had laboratory-confirmed SARS-CoV-2 infection. Among these 426 participants, 184 (43.2%) had symptomatic COVID-19, 383 (89.9%) were not vaccinated or had received only monovalent COVID-19 vaccine doses (1.38 SARS-CoV-2 infections per 1000 person-days), and 43 (10.1%) had received a bivalent COVID-19 vaccine dose (0.84 SARS-CoV-2 infections per 1000 person-days). Bivalent vaccine effectiveness against SARS-CoV-2 infection was 54.0% (95% CI, 36.6%-69.1%) and vaccine effectiveness against symptomatic COVID-19 was 49.4% (95% CI, 22.2%-70.7%). The median observation time after vaccination was 276 days (IQR, 142-350 days) for participants who received only monovalent COVID-19 vaccine doses vs 50 days (IQR, 27-74 days) for those who received a bivalent COVID-19 vaccine dose. The bivalent COVID-19 vaccines protected children and adolescents against SARS-CoV-2 infection and symptomatic COVID-19. These data demonstrate the benefit of COVID-19 vaccine in children and adolescents. All eligible children and adolescents should remain up to date with recommended COVID-19 vaccinations

Research on the Epidemiology of SARS-CoV-2 in Essential Response Personnel (RECOVER): Protocol for a Multisite Longitudinal Cohort Study

BackgroundWorkers critical to emergency response and continuity of essential services during the COVID-19 pandemic are at a disproportionally high risk of SARS-CoV-2 infection. Prospective cohort studies are needed for enhancing the understanding of the incidence of symptomatic and asymptomatic SARS-CoV-2 infections, identifying risk factors, assessing clinical outcomes, and determining the effectiveness of vaccination. ObjectiveThe Research on the Epidemiology of SARS-CoV-2 in Essential Response Personnel (RECOVER) prospective cohort study was designed to estimate the incidence of symptomatic and asymptomatic SARS-CoV-2 infections, examine the risk factors for infection and clinical spectrum of illness, and assess the effectiveness of vaccination among essential workers. MethodsThe RECOVER multisite network was initiated in August 2020 and aims to enroll 3000 health care personnel (HCP), first responders, and other essential and frontline workers (EFWs) at 6 US locations. Data on participant demographics, medical history, and vaccination history are collected at baseline and throughout the study. Active surveillance for the symptoms of COVID-19–like illness (CLI), access of medical care, and symptom duration is performed by text messages, emails, and direct participant or medical record reports. Participants self-collect a mid-turbinate nasal swab weekly, regardless of symptoms, and 2 additional respiratory specimens at the onset of CLI. Blood is collected upon enrollment, every 3 months, approximately 28 days after a reverse transcription polymerase chain reaction (RT-PCR)–confirmed SARS-CoV-2 infection, and 14 to 28 days after a dose of any COVID-19 vaccine. From February 2021, household members of RT-PCR–confirmed participants are self-collecting mid-turbinate nasal swabs daily for 10 days. ResultsThe study observation period began in August 2020 and is expected to continue through spring 2022. There are 2623 actively enrolled RECOVER participants, including 280 participants who have been found to be positive for SARS-CoV-2 by RT-PCR. Enrollment is ongoing at 3 of the 6 study sites. ConclusionsData collected through the cohort are expected to provide important public health information for essential workers at high risk for occupational exposure to SARS-CoV-2 and allow early evaluation of COVID-19 vaccine effectiveness. International Registered Report Identifier (IRRID)DERR1-10.2196/3157

Prevention and Attenuation of COVID-19 by BNT162b2 and mRNA-1273 Vaccines

ABSTRACT BACKGROUND Information is limited on messenger RNA (mRNA) BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccine effectiveness (VE) in preventing SARS-CoV-2 infection or attenuating disease when administered in real-world conditions. METHODS Prospective cohorts of 3,975 healthcare personnel, first responders, and other essential and frontline workers completed weekly SARS-CoV-2 testing during December 14, 2020—April 10 2021. Self-collected mid-turbinate nasal swabs were tested by qualitative and quantitative reverse-transcription–polymerase-chain-reaction (RT-PCR). VE was calculated as 100%×(1−hazard ratio); adjusted VE was calculated using vaccination propensity weights and adjustments for site, occupation, and local virus circulation. RESULTS SARS-CoV-2 was detected in 204 (5.1%) participants; 16 were partially (≥14 days post-dose-1 to 13 days after dose-2) or fully (≥14 days post-dose-2) vaccinated, and 156 were unvaccinated; 32 with indeterminate status ( CONCLUSIONS Authorized mRNA vaccines were highly effective among working-age adults in preventing SARS-CoV-2 infections when administered in real-world conditions and attenuated viral RNA load, febrile symptoms, and illness duration among those with breakthrough infection despite vaccination