Digital and virtual strategies to advance community stakeholder engagement in research during COVID-19 pandemic.

Despite the adversity presented by COVID-19 pandemic, it also pushed for experimenting with innovative strategies for community engagement. The Community Research Advisory Council (C-RAC) at Johns Hopkins University (JHU), is an initiative to promote community engagement in research. COVID-19 rendered it impossible for C-RAC to conduct its meetings all of which have historically been in person. We describe the experience of advancing the work of the C-RAC during COVID-19 using digital and virtual strategies. Since March 2020, C-RAC transitioned from in person to virtual meetings. The needs assessment was conducted among C-RAC members, and individualized solutions provided for a successful virtual engagement. The usual working schedule was altered to respond to COVID-19 and promote community engaged research. Attendance to C-RAC meetings before and after the transition to virtual operation increased from 69% to 76% among C-RAC members from the community. In addition, the C-RAC launched new initiatives and in eighteen months since January 2020, it conducted 50 highly rated research reviews for 20 research teams. The experience of the C-RAC demonstrates that when community needs are assessed and addressed, and technical support is provided, digital strategies can lead to greater community collaborations.

An antibody from single human VH-rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion.

SARS-CoV-2 Omicron subvariants have generated a worldwide health crisis due to resistance to most approved SARS-CoV-2 neutralizing antibodies and evasion of vaccination-induced antibodies. To manage Omicron subvariants and prepare for new ones, additional means of isolating broad and potent humanized SARS-CoV-2 neutralizing antibodies are desirable. Here, we describe a mouse model in which the primary B cell receptor (BCR) repertoire is generated solely through V(D)J recombination of a human VH1-2 heavy chain (HC) and, substantially, a human Vκ1-33 light chain (LC). Thus, primary humanized BCR repertoire diversity in these mice derives from immensely diverse HC and LC antigen-contact CDR3 sequences generated by nontemplated junctional modifications during V(D)J recombination. Immunizing this mouse model with SARS-CoV-2 (Wuhan-Hu-1) spike protein immunogens elicited several VH1-2/Vκ1-33-based neutralizing antibodies that bound RBD in a different mode from each other and from those of many prior patient-derived VH1-2-based neutralizing antibodies. Of these, SP1-77 potently and broadly neutralized all SARS-CoV-2 variants through BA.5. Cryo-EM studies revealed that SP1-77 bound RBD away from the receptor-binding motif via a CDR3-dominated recognition mode. Lattice light-sheet microscopy-based studies showed that SP1-77 did not block ACE2-mediated viral attachment or endocytosis but rather blocked viral-host membrane fusion. The broad and potent SP1-77 neutralization activity and nontraditional mechanism of action suggest that it might have therapeutic potential. Likewise, the SP1-77 binding epitope may inform vaccine strategies. Last, the type of humanized mouse models that we have described may contribute to identifying therapeutic antibodies against future SARS-CoV-2 variants and other pathogens.

Baseline factors associated with self-reported disease flares following COVID-19 vaccination among adults with systemic rheumatic disease: results from the COVID-19 global rheumatology alliance vaccine survey.

OBJECTIVE: To examine the frequency of, and risk factors for, disease flare following COVID-19 vaccination in patients with systemic rheumatic disease (SRD). METHODS: An international study was conducted from 2 April to 16 August 2021, using an online survey of 5619 adults with SRD for adverse events following COVID-19 vaccination, including flares of disease requiring a change in treatment. We examined risk factors identified a priori based on published associations with SRD activity and SARS-CoV-2 severity, including demographics, SRD type, comorbidities, vaccine type, cessation of immunosuppressive medications around vaccination and history of reactions to non-COVID-19 vaccines, using multivariable logistic regression. RESULTS: Flares requiring a change in treatment following COVID-19 vaccination were reported by 4.9% of patients. Compared with rheumatoid arthritis, certain SRD, including systemic lupus erythematosus (OR 1.51, 95% CI 1.03, 2.20), psoriatic arthritis (OR 1.95, 95% CI 1.20, 3.18) and polymyalgia rheumatica (OR 1.94, 95% CI 1.08, 2.48) were associated with higher odds of flare, while idiopathic inflammatory myopathies were associated with lower odds for flare (OR 0.54, 95% CI 0.31-0.96). The Oxford-AstraZeneca vaccine was associated with higher odds of flare relative to the Pfizer-BioNTech vaccine (OR 1.44, 95% CI 1.07, 1.95), as were a prior reaction to a non-COVID-19 vaccine (OR 2.50, 95% CI 1.76, 3.54) and female sex (OR 2.71, 95% CI 1.55, 4.72). CONCLUSION: SRD flares requiring changes in treatment following COVID-19 vaccination were uncommon in this large international study. Several potential risk factors, as well as differences by disease type, warrant further examination in prospective cohorts.

mRNA-encoded HIV-1 Env trimer ferritin nanoparticles induce monoclonal antibodies that neutralize heterologous HIV-1 isolates in mice.

The success of nucleoside-modified mRNAs in lipid nanoparticles (mRNA-LNP) as COVID-19 vaccines heralded a new era of vaccine development. For HIV-1, multivalent envelope (Env) trimer protein nanoparticles are superior immunogens compared with trimers alone for priming of broadly neutralizing antibody (bnAb) B cell lineages. The successful expression of complex multivalent nanoparticle immunogens with mRNAs has not been demonstrated. Here, we show that mRNAs can encode antigenic Env trimers on ferritin nanoparticles that initiate bnAb precursor B cell expansion and induce serum autologous tier 2 neutralizing activity in bnAb precursor VH + VL knock-in mice. Next-generation sequencing demonstrates acquisition of critical mutations, and monoclonal antibodies that neutralize heterologous HIV-1 isolates are isolated. Thus, mRNA-LNP can encode complex immunogens and may be of use in design of germline-targeting and sequential boosting immunogens for HIV-1 vaccine development.

Unusual neurological manifestations in children during the COVID-19 pandemic

Objective: To present paediatric cases of unusual neuroinflammatory conditions encountered during the COVID-19 pandemic in Trinidad & Tobago. Methods: Retrospective study design. Inpatient paediatric patients (aged 0-16 years) hospitalized for neurological complaints from June 2020 - August 2021 at EWMSC. Outcome measures were age at presentation, sex, ethnicity, diagnosis, radiological findings, blood/CSF findings, COVID-19 PCR and antibodies testing, treatment, outcomes and other systems involved. Results: Twenty (20) patients (aged 4-months-old to 15-years-old) had documented neurological involvement. 50% had a diagnosis of ADEM/ADS/AHNE;45% had a diagnosis of either CNS vasculitis (n=3), autoimmune encephalitis (n=3) or GBS (n=3);5% had a diagnosis of acute COVID-19 encephalitis. 70% were of African descent. The youngest age group (0-4 years) (n=11) constituted more males (82%) whereas the eldest age group (10-15 years) (n=3) were all females. Neuroimaging findings were corpus callosal lesions;deep white matter T2 hyperintensities;cerebellar involvement;area postrema and brainstem/C-spine involvement;microhaemorrhages and necrotizing/haemorrhagic lesions (peripheral/central). 70% of patients were either SARS-CoV-2 PCR or COVID-19 antibodies positive. Other systems were involved in 40% to 62.5% (n=5) had cardiac involvement (myocarditis, coronary arteries dilatation, valve regurgitation) and 37.5% (n=3) had pancreatic involvement (autoimmune pancreatitis, type 1 diabetes mellitus). Treatment modalities for CNS manifestations (n=17) were clinically based - 24% (n=4) 3rd line treatment, 29% (n=5) 2nd line treatment, 41% (n=7) 1st line treatment and 6% (n=1) requiring no treatment. All 3 patients with a diagnosis of GBS responded appropriately to IVIG. Developmental outcomes were worst in patients with a diagnosis of autoimmune encephalitis. Conclusion: We have had an explosion of neuro-inflammatory cases since the COVID-19 pandemic began. The range of neuroradiological diagnoses and other systemic involvement (including criteria for PIMS) are interesting, alluding to a neuroinflammatory mechanism. Effects on long-term sequelae and developmental outcomes are concerning in some cases, however, still unknown at this stage.

A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic

Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo , Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro , SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.

A High-Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury.

Drug repurposing has the advantage of identifying potential treatments on a shortened timescale. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high-content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce mucin-1 (MUC1) protein abundance. Elevated MUC1 levels predict the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and correlate with poor clinical outcomes. Our screen identifies fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, fostamatinib reduces MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by the active metabolite R406 promotes MUC1 removal from the cell surface. Our work suggests fostamatinib as a repurposing drug candidate for ALI.

Comparative analysis of viral infection outcomes in human seminal fluid from prior viral epidemics and Sars-CoV-2 may offer trends for viral sexual transmissibility and long-term reproductive health implications.

BACKGROUND: Viral detection in seminal fluid indicates their potential for both sexual transmission and impairment of reproductive health. Review of the mechanistic entry, sexual transmission and viral impacts for patients during major recent viral outbreaks of Zika virus (ZIKV), Ebola virus (EBOV), severe acute respiratory syndrome (SARS)-coronavirus (CoV), and SARS-coronavirus 2 (CoV-2) (the virus which causes COVID-19) provides a framework to discuss this potential. AIM: Comparative analysis of prior viral presence on seminal fluid against current (preliminary) findings for SARS-CoV-2 to predict biological implications of the novel coronavirus upon current sexual transmissibility, viral presence, and reproductive health. METHODOLOGY AND FINDINGS: Literature review was conducted using PubMed and Google Scholar databases. ZIKV and EBOV were found to be present in semen and to be sexually transmitted, leading the World Health Organization (WHO) to update their guidelines on prevention of the two viruses to include refraining from sexual contact. There are conflicting studies regarding the presence of SARS-CoV in male reproductive tissue, but it has been linked to testicular atrophy and orchitis. To date, two studies have detected SARS-CoV-2 RNA in semen, while seven studies have reported no positive detection. CONCLUSIONS: Though unlikely in the majority of cases, SARS-CoV-2 can potentially be present in seminal fluid, although there are no reports of sexual transmission to date. Prior epidemics raise significant concerns regarding the long-term reproductive health capacity for patients who are affected by entry of Sars-CoV-2 into the reproductive tract, therefore more study is needed to clarify the impacts to reproductive health.

This review describes the detection of viruses in seminal fluid and their sexual transmission, focusing on the major viral outbreaks of Zika virus (ZIKV), Ebola virus (EBOV), severe acute respiratory syndrome (SARS)-coronavirus (CoV), and SARS-coronavirus 2 (CoV-2). ZIKV and EBOV were found to be present in semen and to be sexually transmitted, leading the World Health Organization (WHO) to update their guidelines on prevention of the two viruses to include refraining from sexual contact. There are conflicting studies regarding the presence of SARS-CoV in male reproductive tissue, but it has been linked to testicular atrophy and orchitis. To date, two studies have detected SARS-CoV-2 RNA in semen, while seven studies have reported no positive detection. More studies must be completed to accurately determine its risk of sexual transmission to ensure mitigation of further transmission and understand the long-term implications of SARS-CoV-2 on the reproductive health of recovered patients.

COVID-19 and the Environment, Review and Analysis

We reviewed studies linking COVID-19 cases and deaths with the environment, focusing on relationships with air pollution. We found both short- and long-term observational relationships with a range of regulated pollutants, although only two studies considered both cases (i.e., infections) and deaths within a common analytical framework. Most of these studies were limited to a few months of the pandemic period. Statistically significant relationships were found more often for PM2.5 and NO2 than for other regulated pollutants, but no rationale was suggested for such short-term relationships;latency was seldom considered for long-term relationships. It was also unclear whether confounding had been adequately controlled in either type of study. Studies of air quality improvement following lockdowns found more robust relationships with local (CO, NO2) rather than regional (PM2.5, O3) pollutants, but meteorological confounding was seldom considered. Only one of seven studies of airborne virus transmission reported actual measurements. Overall, we found the existing body of literature to be more suggestive than definitive. Due to these various deficiencies, we assembled a new state-level database of cumulative COVID-19 cases and deaths through March 2021 with a range of potential predictor variables and performed linear regression analyses on various combinations. As single predictors, we found significant (p <0.05) relationships between cumulative cases and household crowding (+), education (−), face-mask usage (−), or voting Republican (+). For cumulative deaths, we found significant relationships with education (−), black race (+), or previous levels of PM2.5 (+). NOx (+), and elemental carbon (EC, +). We found no relationships between long-term air quality and cumulative COVID-19 cases. Our associations linking air pollution with COVID-19 mortality were not statistically different from those for all-cause mortality in previous studies. In multiple mortality regressions combining air pollution, race, and education, NOx and EC remained significant but PM2.5 did not. We concluded that the current worldwide emphasis on PM2.5 is misplaced. We predicted air pollutant effects of a few percentage points, but individual differences between races, political identification, and post-graduate education were of the order of factors of 2 to 4. In general, the factors predicting infection were personal and related to COVID-19 exposure, while those predicting subsequent mortality tended to be more situational and related to geography. Overall, we concluded that how you live is more important than where you live.

A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic.

Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo , Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro , SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.

A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic (preprint)

Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.