Immune profiling of SARS-CoV-2 infection during pregnancy reveals NK cell and γδ T cell perturbations.

Pregnancy poses a greater risk for severe COVID-19; however, underlying immunological changes associated with SARS-CoV-2 during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in unvaccinated pregnant and nonpregnant women with acute and convalescent COVID-19, quantifying 217 immunological parameters. Humoral responses to SARS-CoV-2 were similar in pregnant and nonpregnant women, although our systems serology approach revealed distinct antibody and FcγR profiles between pregnant and nonpregnant women. Cellular analyses demonstrated marked differences in NK cell and unconventional T cell activation dynamics in pregnant women. Healthy pregnant women displayed preactivated NK cells and γδ T cells when compared with healthy nonpregnant women, which remained unchanged during acute and convalescent COVID-19. Conversely, nonpregnant women had prototypical activation of NK and γδ T cells. Activation of CD4+ and CD8+ T cells and T follicular helper cells was similar in SARS-CoV-2-infected pregnant and nonpregnant women, while antibody-secreting B cells were increased in pregnant women during acute COVID-19. Elevated levels of IL-8, IL-10, and IL-18 were found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, we demonstrate perturbations in NK cell and γδ T cell activation in unvaccinated pregnant women with COVID-19, which may impact disease progression and severity during pregnancy.

Fear of COVID-19 is associated with trust, subjective numeracy, and differentially with loneliness in older versus younger adults.

Introduction: The emotional impacts of the COVID-19 pandemic and resulting public health emergency are only beginning to be understood. Methods: We assessed the contributions of emotional and cognitive factors and age-related comorbidities to greater COVID-19 fear in a community dwelling sample of 142 younger (Mage = 19.63, SDage = 2.59) and 157 older (Mage = 72.01, SDage = 7.06) adults, between July 2020 and July 2021. We hypothesized that individuals with increased loneliness, depression, and/or decreased subjective numeracy (SN) and interpersonal trust would experience more COVID-19 fear. We also predicted that females and older adults would experience more COVID-19 fear given that age-related comorbidities are associated with increased illness severity. Results: Results showed that the extent of loneliness in older adults was more strongly related to fear of COVID-19 than it was in younger adults (ß = 0.197, p = 0.016), and poorer SN was associated with increased COVID-19 fear in both age groups (ß = -0.138, p = 0.016). Further, higher interpersonal mistrust was associated with increased COVID-19 fear (ß = 0.136, p = 0.039), as was identifying as female (ß = 0.137, p = 0.013). Discussion: Given that self-described poor numeracy was a marker for greater COVID-19 fear, investigators and policy makers might consider mitigation opportunities addressing data literacy requirements imposed by the media. Further, outreach to mitigate loneliness, particularly of the elderly, might effectively lessen the negative psychological impact of this ongoing public health crisis.

How a Community Approach Can Drive Pharmacovigilance Activities in Low-Resource Settings during a Public Health Emergency: Lessons from COVID-19

Introduction: Undertaking effective drug safety monitoring can be particularly challenging in low-resource settings due to a lack of infrastructure, weak regulatory systems and poor access to training and education [1]. Given the continued impact the COVID-19 pandemic is having upon health systems globally, it is essential to ensure that pharmacovigilance systems in these vulnerable settings have the capacity to address both the exacerbated pre-existing and novel challenges that they now face [2]. This project seeks to harness the membership of an online pharmacovigilance platform, globalpharmacovigilance. org (GPV) to work together in a 'community of practice' (CoP) on specific challenges facing pharmacovigilance during the pandemic [3, 4]. Objective(s): To gather consensus on pharmacovigilance priorities in low-resource settings during the COVID-19 pandemic and provide resources to address them using a CoP model. Method(s): This project has built on a consensus-gathering methodology developed by The Global Health Network that has been implemented successfully during the pandemic to address wider COVID-19 research priorities. An online survey of GPV members was used to identify highly-ranked areas for pharmacovigilance improvement in low-resource settings during the pandemic. A virtual workshop was then hosted to invite further discussion on the survey results and reach consensus on the highest priorities. Members of the CoP were next invited to form virtual working groups, each focussing on one of the top 3 priorities identified. These groups are being supported by GPV to work together and facilitate the development (or provision, if pre-existing) of pharmacovigilance resources to address the priorities identified. Result(s): Of the 43 pharmacovigilance 'themes' that were presented to the CoP membership in the initial survey, 3 topics were identified as the highest priorities at that point in the COVID-19 pandemic, where support, training and guidance are needed;'The safety of COVID-19 vaccination in pregnancy', 'The safety of COVID-19 vaccination in children/adolescents' and 'Analysis of COVID-19 vaccine safety data'. As of May 2022, the number of GPV members interested in involvement in working groups addressing these themes are 207, 206, and 284 respectively. Initial group meetings took place in April 2022 and discussions are ongoing as to how to take group activities forward and address the priorities identified. Conclusion(s): A CoP model represents an effective method of consensus gathering amongst pharmacovigilance stakeholders at a global level, and allows rapid identification of healthcare priorities during public health emergencies. It is anticipated that working groups outputs will include the provision of resources designed to address the priorities identified.

SARS-CoV-2-specific T cell memory with common TCRαß motifs is established in unvaccinated children who seroconvert after infection.

As the establishment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory in children remains largely unexplored, we recruited convalescent COVID-19 children and adults to define their circulating memory SARS-CoV-2-specific CD4+ and CD8+ T cells prior to vaccination. We analyzed epitope-specific T cells directly ex vivo using seven HLA class I and class II tetramers presenting SARS-CoV-2 epitopes, together with Spike-specific B cells. Unvaccinated children who seroconverted had comparable Spike-specific but lower ORF1a- and N-specific memory T cell responses compared with adults. This agreed with our TCR sequencing data showing reduced clonal expansion in children. A strong stem cell memory phenotype and common T cell receptor motifs were detected within tetramer-specific T cells in seroconverted children. Conversely, children who did not seroconvert had tetramer-specific T cells of predominantly naive phenotypes and diverse TCRαß repertoires. Our study demonstrates the generation of SARS-CoV-2-specific T cell memory with common TCRαß motifs in unvaccinated seroconverted children after their first virus encounter.

Prediction of Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infection by Quantitative Digital Polymerase Chain Reaction Normalized to International Units.

Although numerous studies have evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using cycle threshold (Ct) values as a surrogate of viral ribonucleic acid (RNA) load, few studies have used standardized, quantitative methods. We validated a quantitative SARS-CoV-2 digital polymerase chain reaction assay normalized to World Health Organization International Units and correlated viral RNA load with symptoms and disease severity.

How a Community Approach Can Drive Pharmacovigilance Activities in Low-Resource Settings during a Public Health Emergency: Lessons from COVID-19: An International Journal of Medical Toxicology and Drug Experience

Introduction: Undertaking effective drug safety monitoring can be particularly challenging in low-resource settings due to a lack of infrastructure, weak regulatory systems and poor access to training and education [1]. Given the continued impact the COVID-19 pandemic is having upon health systems globally, it is essential to ensure that pharmacovigilance systems in these vulnerable settings have the capacity to address both the exacerbated pre-existing and novel challenges that they now face [2]. This project seeks to harness the membership of an online pharmacovigilance platform, globalpharmacovigilance.org (GPV) to work together in a 'community of practice' (CoP) on specific challenges facing pharmacovigilance during the pandemic [3, 4]. Objective: To gather consensus on pharmacovigilance priorities in low-resource settings during the COVID-19 pandemic and provide resources to address them using a CoP model. Methods: This project has built on a consensus-gathering methodology developed by The Global Health Network that has been implemented successfully during the pandemic to address wider COVID-19 research priorities. An online survey of GPV members was used to identify highly-ranked areas for pharmacovigilance improvement in low-resource settings during the pandemic. A virtual workshop was then hosted to invite further discussion on the survey results and reach consensus on the highest priorities. Members of the CoP were next invited to form virtual working groups, each focussing on one of the top 3 priorities identified. These groups are being supported by GPV to work together and facilitate the development (or provision, if pre-existing) of pharmacovigilance resources to address the priorities identified. Results: Of the 43 pharmacovigilance 'themes' that were presented to the CoP membership in the initial survey, 3 topics were identified as the highest priorities at that point in the COVID-19 pandemic, where support, training and guidance are needed;'The safety of COVID-19 vaccination in pregnancy', 'The safety of COVID-19 vaccination in children/adolescents' and 'Analysis of COVID-19 vaccine safety data'. As of May 2022, the number of GPV members interested in involvement in working groups addressing these themes are 207, 206, and 284 respectively. Initial group meetings took place in April 2022 and discussions are ongoing as to how to take group activities forward and address the priorities identified. Conclusion: A CoP model represents an effective method of consensus gathering amongst pharmacovigilance stakeholders at a global level, and allows rapid identification of healthcare priorities during public health emergencies. It is anticipated that working groups outputs will include the provision of resources designed to address the priorities identified.

Mucin Transiently Sustains Coronavirus Infectivity through Heterogenous Changes in Phase Morphology of Evaporating Aerosol.

Respiratory pathogens can be spread though the transmission of aerosolised expiratory secretions in the form of droplets or particulates. Understanding the fundamental aerosol parameters that govern how such pathogens survive whilst airborne is essential to understanding and developing methods of restricting their dissemination. Pathogen viability measurements made using Controlled Electrodynamic Levitation and Extraction of Bioaerosol onto Substrate (CELEBS) in tandem with a comparative kinetics electrodynamic balance (CKEDB) measurements allow for a direct comparison between viral viability and evaporation kinetics of the aerosol with a time resolution of seconds. Here, we report the airborne survival of mouse hepatitis virus (MHV) and determine a comparable loss of infectivity in the aerosol phase to our previous observations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through the addition of clinically relevant concentrations of mucin to the bioaerosol, there is a transient mitigation of the loss of viral infectivity at 40% RH. Increased concentrations of mucin promoted heterogenous phase change during aerosol evaporation, characterised as the formation of inclusions within the host droplet. This research demonstrates the role of mucus in the aerosol phase and its influence on short-term airborne viral stability.

The dynamics of SARS-CoV-2 infectivity with changes in aerosol microenvironment.

Understanding the factors that influence the airborne survival of viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in aerosols is important for identifying routes of transmission and the value of various mitigation strategies for preventing transmission. We present measurements of the stability of SARS-CoV-2 in aerosol droplets (∼5 to 10 µm equilibrated radius) over timescales spanning 5 s to 20 min using an instrument to probe survival in a small population of droplets (typically 5 to 10) containing ∼1 virus/droplet. Measurements of airborne infectivity change are coupled with a detailed physicochemical analysis of the airborne droplets containing the virus. A decrease in infectivity to ∼10% of the starting value was observable for SARS-CoV-2 over 20 min, with a large proportion of the loss occurring within the first 5 min after aerosolization. The initial rate of infectivity loss was found to correlate with physical transformation of the equilibrating droplet; salts within the droplets crystallize at relative humidities (RHs) below 50%, leading to a near-instant loss of infectivity in 50 to 60% of the virus. However, at 90% RH, the droplet remains homogenous and aqueous, and the viral stability is sustained for the first 2 min, beyond which it decays to only 10% remaining infectious after 10 min. The loss of infectivity at high RH is consistent with an elevation in the pH of the droplets, caused by volatilization of CO2 from bicarbonate buffer within the droplet. Four different variants of SARS-CoV-2 were compared and found to have a similar degree of airborne stability at both high and low RH.

Host Predictors of Broadly Cross-Reactive Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants of Concern Differ Between Infection and Vaccination.

BACKGROUND: Following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination there is significant variability between individuals in protective antibody levels against SARS-CoV-2, and within individuals against different virus variants. However, host demographic or clinical characteristics that predict variability in cross-reactive antibody levels are not well-described. These data could inform clinicians, researchers, and policymakers on the populations most likely to require vaccine booster shots. METHODS: In an institutional review board-approved prospective observational cohort study of staff at St. Jude Children's Research Hospital, we identified participants with plasma samples collected after SARS-CoV-2 infection, after mRNA vaccination, and after vaccination following infection, and quantitated immunoglobulin G (IgG) levels by enzyme-linked immunosorbent assay to the spike receptor binding domain (RBD) from 5 important SARS-CoV-2 variants (Wuhan Hu-1, B.1.1.7, B.1.351, P.1, and B.1.617.2). We used regression models to identify factors that contributed to cross-reactive IgG against 1 or multiple viral variants. RESULTS: Following infection, a minority of the cohort generated cross-reactive antibodies, IgG antibodies that bound all tested variants. Those who did had increased disease severity, poor metabolic health, and were of a particular ancestry. Vaccination increased the levels of cross-reactive IgG levels in all populations, including immunocompromised, elderly, and persons with poor metabolic health. Younger people with a healthy weight mounted the highest responses. CONCLUSIONS: Our findings provide important new information on individual antibody responses to infection/vaccination that could inform clinicians on populations that may require follow-on immunization.

Mucosal immune responses to infection and vaccination in the respiratory tract.

The lungs are constantly exposed to inhaled debris, allergens, pollutants, commensal or pathogenic microorganisms, and respiratory viruses. As a result, innate and adaptive immune responses in the respiratory tract are tightly regulated and are in continual flux between states of enhanced pathogen clearance, immune-modulation, and tissue repair. New single-cell-sequencing techniques are expanding our knowledge of airway cellular complexity and the nuanced connections between structural and immune cell compartments. Understanding these varied interactions is critical in treatment of human pulmonary disease and infections and in next-generation vaccine design. Here, we review the innate and adaptive immune responses in the lung and airways following infection and vaccination, with particular focus on influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ongoing SARS-CoV-2 pandemic has put pulmonary research firmly into the global spotlight, challenging previously held notions of respiratory immunity and helping identify new populations at high risk for respiratory distress.

SARS-CoV-2 Transmission Dynamics in Households With Children, Los Angeles, California.

Objectives: Studies of household transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) focused on households with children are limited. We investigated household secondary attack rate (SAR), transmission dynamics, and contributing factors in households with children. Materials and Methods: In this prospective case-ascertained study in Los Angeles County, California, all households members were enrolled if ≥1 member tested positive for SARS-CoV-2 by polymerase chain reaction (PCR). Nasopharyngeal PCRs, serology, and symptom data were obtained over multiple visits. Results: A total of 489 individuals in 105 households were enrolled from June to December 2020. The majority (77.3%) reported a household annual income of <$50,000, and most (92.9%) were of Hispanic/Latinx ethnicity. Children <18 years old accounted for 46.9% index cases, of whom 45.3% were asymptomatic. Household index cases were predominantly children during low community transmission and adults during the high community transmission period (χ2 = 7.647, p = 0.0036. The mean household SAR was 77.0% (95% CI: 69.4-84.6%). Child and adult index cases both efficiently transmitted SARS-CoV-2 within households [81.9%, (95% CI: 72.1-91.9%) vs. 72.4% (95% CI: 59.8-85.1%), p = 0.23]. Household income and pets were significantly associated with higher SAR in the multivariable analysis of household factors (p = 0.0013 and 0.004, respectively). Conclusions: The SAR in households with children in an urban setting with a large ethnic minority population is much higher than previously described. Children play important roles as index cases. SAR was disproportionately impacted by household income. Vaccination and public health efforts need special focus on children and vulnerable communities to help mitigate SARS-CoV-2 spread.

A randomized phase II trial of carboplatin with or without nivolumab in metastatic triple-negative breast cancer

Background: Platinum agents induce DNA crosslinking and cause accumulation of genotoxic stress, which leads to immune activation via IFN-γ signaling, making the combination with nivolumab (PD-1 antibody) an attractive strategy to enhance the benefit of either agent alone in metastatic triple-negative breast cancer (mTNBC). Methods: In this phase II open-label, investigator-initiated, multicenter trial, patients with unresectable locally advanced or mTNBC treated with 0-1 prior lines of chemotherapy in the metastatic setting were randomized 1:1 to carboplatin (AUC 6) with or without nivolumab (360 mg) IV every 3 weeks. Stratification factors included: germline BRCA (gBRCA) status, prior neo/adjuvant platinum, and number of prior lines of metastatic therapy. After approval of PD-L1 inhibition for mTNBC, the study was amended to include first-line mTNBC only and PD-L1 status was added as a stratification factor. Patients randomized to carboplatin alone were allowed to crossover at progression to receive nivolumab (+ nab-paclitaxel post-amendment). The primary objective was to compare progression-free survival (PFS) per RECIST 1.1 criteria of carboplatin with or without nivolumab in first-line mTNBC in the S intent-to-treat (ITT) population. Key secondary objectives were objective response rate (ORR), overall survival (OS), clinical benefit rate, and duration and time to objective response. PD-L1 status was confirmed centrally using the SP142 Ventana assay (positive, ≥1% IC). Paired researchbiopsies at baseline, on-treatment and at progression were performed, if safely accessible. The trial closed to accrual prior to reaching target accrual due to approval of PD-1 inhibition in combination with platinum-based chemotherapy for PD-L1+ mTNBC. Results: Between 1/30/2018 and 12/9/2020, 78 patients enrolled. Three patients did not receive protocol treatment, and the safety analysis was conducted among the 75 that received any treatment;37 received carboplatin + nivolumab (Arm A), 38 received carboplatin alone (Arm B). Median age was 59.1 yrs (range: 25.4-75.8). Four patients (5.3%) had a known gBRCA1/2 mutation. Sixty-two (82.7%) patients received 0 prior lines (ITT population) and 13 (17.3%) 1 prior line of metastatic therapy. Sixty-seven patients (89.3%) experienced any grade ≥2 treatment-related adverse event (AE). The most frequent AE were platelet count decrease (n=40;53.3%), anemia (n=36;48.0%), neutrophil count decrease (n=33;44.0%) and fatigue (n=24;32.0%). Grade 3/4 AE were observed in 46 (61.3%) patients, and there was one grade 5 AE (COVID19 pneumonia). Any grade ≥2 immune-related AE (irAE) were observed in 25 of the 37 (67.6%) patients treated with carboplatin + nivolumab. Grade 3/4 irAE were observed in 11 (29.7%) patients. In the ITT population (32 on Arm A;30 on Arm B), median PFS was 4.2 months with carboplatin + nivolumab, and 5.5 months with carboplatin (stratified HR 0.98, 95% CI [0.51-1.88];p=0.95). ORR was 25% vs. 23.3%, respectively. At a median follow-up of 23.5 months, median OS was 17.5 months vs. 10.7 months (stratified HR 0.63, 95% CI [0.32-1.24];p=0.18). In patients with PD-L1+ mTNBC (13 on Arm A;11 on Arm B), median PFS was 8.3 months and 4.7 months, respectively (stratified HR 0.63, 95% CI [0.21-1.89];p=0.41). ORR was 23.1% vs. 27.3%, respectively. Median OS was 17.5 months vs. 9.6 months (stratified HR 0.59, 95% CI [0.20-1.75];p=0.34). Conclusions: Addition of nivolumab to carboplatin in patients with previously untreated mTNBC, unselected by PD-L1 status, did not significantly improve PFS. A trend toward improved PFS and OS was observed in patients with PD-L1+ mTNBC. Tissue, blood and intestinal microbiome biomarker analyses are planned;bulk tumor and single-cell sequencing, and TCR sequencing in peripheral blood are ongoing.

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8+ T cells.

Although mRNA vaccine efficacy against severe coronavirus disease 2019 remains high, variant emergence has prompted booster immunizations. However, the effects of repeated exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens on memory T cells are poorly understood. Here, we utilize major histocompatibility complex multimers with single-cell RNA sequencing to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two or three antigen exposures, including vaccination, primary infection and breakthrough infection. Exposure order determined the distribution between spike-specific and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7-CD45RA+ effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell antigen receptor (TCR) sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory.

Longitudinal Plasma Cytokine Profiles Differentiating COVID-19 Severity Groups

Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infection with widely varying clinical severity. Severe COVID-19 was initially proposed to be secondary to cytokine storm syndrome (CSS). However, studies since showed that patients with severe COVID-19 rarely display CSS cytokine phenotypes, and may have more limited inflammatory responses instead. Methods. Prospective cohorts, aged 0-90 years of age who tested positive by polymerase chain reaction (PCR) for SARS-CoV-2 were enrolled from inpatient hospitals and outpatient testing centers in Memphis, TN from May 2020-January 2021. Longitudinal blood samples were obtained including acute, sub-acute and convalescent timepoints. Severity scores of asymptomatic, mild, moderate, and severe COVID-19 were assigned at time of convalescent assessment. Plasma was analyzed with a quantitative human magnetic 38-plex cytokine assay. Results. : 169 participants were enrolled, including 8 asymptomatic, 117 mild, 22 moderate and 17 severe cases, and 5 children with post-COVID-19 multisystem inflammatory syndrome in children (MIS-C). All moderate and severe patients were hospitalized and received treatment (39%). Clear distinctions were seen between asymptomatic-mild cases and moderate-severe cases at acute timepoints and during disease progression for GCSF, IL-8, IL-10, IL-15, IL-1Ra, IP-10, MIP-1a, MIP-1β, and TGFα. There was a significant difference between participants who did and did not require hospitalization for acute timepoint levels of IL-10, IL-15, MIP-1 β and TGFα (p< 0.01). Only 4 participants with active COVID-19 were found to meet criteria for CSS (2%), only 3 of which were severe. MIS-C participants showed nearly universally elevated cytokine levels compared to those with active COVID-19. Conclusion. Moderate and severe acute COVID-19 has a distinct cytokine profile from asymptomatic and mild cases, as detected from acute, subacute and convalescent plasma.

Pre-existing humoral immunity to human common cold coronaviruses negatively impacts the protective SARS-CoV-2 antibody response.

SARS-CoV-2 infection causes diverse outcomes ranging from asymptomatic infection to respiratory distress and death. A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoVs) impacts susceptibility to SARS-CoV-2 infection or immunity following infection and vaccination. Therefore, we analyzed samples from the same individuals before and after SARS-CoV-2 infection or vaccination. We found hCCCoV antibody levels increase after SARS-CoV-2 exposure, demonstrating cross-reactivity. However, a case-control study indicates that baseline hCCCoV antibody levels are not associated with protection against SARS-CoV-2 infection. Rather, higher magnitudes of pre-existing betacoronavirus antibodies correlate with more SARS-CoV-2 antibodies following infection, an indicator of greater disease severity. Additionally, immunization with hCCCoV spike proteins before SARS-CoV-2 immunization impedes the generation of SARS-CoV-2-neutralizing antibodies in mice. Together, these data suggest that pre-existing hCCCoV antibodies hinder SARS-CoV-2 antibody-based immunity following infection and provide insight on how pre-existing coronavirus immunity impacts SARS-CoV-2 infection, which is critical considering emerging variants.

The impactof COVID-19 restrictions on participant enrollment in the prepare trial

Introduction: PREPARE is a pragmatic clusterrandomized crossover trial that compares the effectiveness of two common pre-operative antiseptic skin solutions to reduce the risk of surgical site infection after orthopedic fracture surgery. The trial compares 2% chlorhexidine in 70% isopropyl alcohol (ChloraPrep™) versus 0.7% iodine povacrylex in 74% isopropyl alcohol (DuraPrep™), and recruiting sites alternate study solutions every 2 months. Before the US national response to the COVID-19 pandemic, all PREPARE trial clinical sites obtained informed consent in person at the hospitals or fracture clinics. However, after 13 March 2020, the COVID-19 restrictions limited inperson consenting at some hospitals. Affected clinical sites were encouraged to transition to telephone consent, which was already included as a consent option in the PREPARE protocol. We aimed to determine how COVID-19 restrictions impacted the number of enrolling clinical sites and participant enrollment in the PREPARE trial. Methods: Prior to implementing telephone consent, clinical sites had to determine local logistics and obtain institutional review board approval for telephone consent scripts and procedures from the central or local institutional review boards. We descriptively evaluated the number of clinical sites that switched to telephone consent, the number of clinical sites that had to pause enrollment, and the length of the enrollment pauses. We evaluated monthly enrollment at the following time periods: (1) prior to the COVID-19 restrictions (1 July 2019 to 13 March 2020), (2) immediately after the COVID-19 restrictions in place (March, April, and May 2020), and (3) from 1 June 2020 to 30 November 2020. Results are stratified by open and closed fractures and are summarized using descriptive statistics. Results: At the time of the pandemic, 13 clinical sites were participating in the PREPARE trial. Eleven (84.6%) clinical sites paused enrollment due to COVID- 19 restrictions. The median length of enrollment pause was 44 days (range = 7-92 days;interquartile range = 54 days). By 16 June 2020, all clinical sites resumed enrollment. The average monthly enrollment before the COVID-19 restrictions was 198 closed fracture participants (SD = 22, range = 161-227) and 41 open fracture participants (SD = 16, range = 22-60). The enrollment rate was the lowest in April 2020, when 47 closed fracture participants and nine open fracture participants were enrolled. By June 2020, enrollment began increasing. From 1 June 2020 to 30 November 2020, the average monthly enrollment rate was 183 closed fracture participants (SD = 30, range = 129-206) and 44 open fracture participants (SD = 12, range = 24-61), which was close to pre-COVID enrollment. Monthly enrollment between 2019 and 2020 was similar, except for the months of March to May 2020 for closed fracture enrollment (p = 0.001) and March and April 2020 for open fracture enrollment (p = 0.04) cohorts. Conclusion: By pre-emptively including telephone consent in the PREPARE protocol, clinical sites were quickly and ethically adapting their procedures for obtaining informed consent via telephone. Although multiple sites paused enrollment, the enrollment pause was brief and had minimal impact on enrollment. A highly pragmatic design allowed for minimal interruptions to enrollment during the pandemic.

Pre-existing humoral immunity to human common cold coronaviruses negatively impacts the protective SARS-CoV-2 antibody response

A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoV) impacts susceptibility to SARS-CoV-2 infection. Lin et al. analyze hCCCoV antibodies in the same individuals before and after SARS-CoV-2 infection, finding pre-existing betacoronavirus antibodies may hinder SARS-CoV-2 effective immunity following infection.

Identifying Priorities for Pharmacovigilance in Low- Resource Settings During the COVID-19 Pandemic: A Community of Practice Approach: An International Journal of Medical Toxicology and Drug Experience

Background/Introduction: Undertaking effective drug safety monitoring is particularly challenging in low-resource settings due to a lack of infrastructure, weak regulatory systems and poor access to training and education [1]. Given the impact that the COVID-19 pandemic is having upon health systems globally, it is essential to ensure that pharmacovigilance systems in these vulnerable settings have the capacity to address both the exacerbated pre-existing and novel challenges that they now face [2]. This project will harness the membership of an online pharmacovigilance platform, globalpharmacovigilance.org (GPV) to create a community of practice (CoP) to address the challenges facing pharmacovigilance during the pandemic[3, 4]. This community can use proven approaches to reach strong and highly democratic consensus on pharmacovigilance priorities, and then provide relevant resources (whether existing or new training, guidance, tools, mentoring) to address the gaps. The online platform will be used by the CoP to share best practices, engage more widely and disseminate outputs and guidance. Objective/Aim: To identify priorities for pharmacovigilance in low-resource settings during the COVID-19 pandemic and provide resources to address these within a CoP model. Methods: This project will build on a consensus-gathering methodology developed by The Global Health Network that has been implemented successfully during the pandemic to address wider COVID-19 research priorities. An online survey, distributed via social media, mailing lists and directly on GPV, will be used to identify priority areas for pharmacovigilance improvement in low-resource settings. Participants will then be invited to attend an online open workshop, in which the survey results will be presented and consensus gathered on an area for focus. Attendees will be invited to form a working group(s). Membership will be self-selective to encourage involvement from all experience levels. This working group(s) will then be supported to work together to facilitate the development of (or provision of, if already available elsewhere) pharmacovigilance resources to address the priorities identified. Results: Results will be presented in the form of a knowledge gap analysis for pharmacovigilance in low-resource settings during the COVID-19 pandemic, consisting of qualitative/quantitative results from the survey and qualitative data from the workshop. Qualitative/ quantitative data on the uptake and use of the GPV platform will also be presented. Conclusion: It is anticipated that findings will help to understand whether and how a CoP may be built and engaged with using an online platform during a pandemic, and then contribute to a priority area for improvement or development within pharmacovigilance at that time.