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BACKGROUNDCOVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODSThis secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization-equivalent anti-Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis.RESULTSSARS-CoV-2 anti-S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01).CONCLUSIONIn unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors' antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use.TRIAL REGISTRATIONClinicalTrials.gov NCT04373460.FUNDINGDepartment of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

SARS-CoV-2 infection during pregnancy is associated with severe COVID-19 and adverse fetal outcomes, but the underlying mechanisms remain poorly understood. Moreover, clinical studies assessing therapeutics against SARS-CoV-2 in pregnancy are limited. To address these gaps, we developed a mouse model of SARS-CoV-2 infection during pregnancy. Outbred CD1 mice were infected at E6, E10, or E16 with a mouse-adapted SARS-CoV-2 (maSCV2) virus. Outcomes were gestational age-dependent, with greater morbidity, reduced antiviral immunity, greater viral titers, and impaired fetal growth and neurodevelopment occurring with infection at E16 (third trimester equivalent) than with infection at either E6 (first trimester equivalent) or E10 (second trimester equivalent). To assess the efficacy of ritonavir-boosted nirmatrelvir, which is recommended for individuals who are pregnant with COVID-19, we treated E16-infected dams with mouse-equivalent doses of nirmatrelvir and ritonavir. Treatment reduced pulmonary viral titers, decreased maternal morbidity, and prevented offspring growth restriction and neurodevelopmental impairments. Our results highlight that severe COVID-19 during pregnancy and fetal growth restriction is associated with heightened virus replication in maternal lungs. Ritonavir-boosted nirmatrelvir mitigated maternal morbidity along with fetal growth and neurodevelopment restriction after SARS-CoV-2 infection. These findings prompt the need for further consideration of pregnancy in preclinical and clinical studies of therapeutics against viral infections.

Understanding the mechanisms of antibody-mediated neutralization of SARS-CoV-2 is critical in combating the COVID-19 pandemic. Based on previous reports of antibody catalysis, we investigated the proteolysis of spike (S) by antibodies in COVID-19 convalescent plasma (CCP) and its contribution to viral neutralization. Quenched fluorescent peptides were designed based on S epitopes to sensitively detect antibody-mediated proteolysis. We observed epitope cleavage by CCP from different donors which persisted when plasma was heat-treated or when IgG was isolated from plasma. Further, purified CCP antibodies proteolyzed recombinant S domains, as well as authentic viral S. Cleavage of S variants suggests CCP antibody-mediated proteolysis is a durable phenomenon despite antigenic drift. We differentiated viral neutralization occurring via direct interference with receptor binding from that occurring by antibody-mediated proteolysis, demonstrating that antibody catalysis enhanced neutralization. These results suggest that antibody-catalyzed damage of S is an immunologically relevant function of neutralizing antibodies against SARS-CoV-2., Competing Interests: Declaration of interests None declared., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Benchmarks for protective immunity from infection or severe disease after SARS-CoV-2 vaccination are still being defined. Here, we characterized virus neutralizing and ELISA antibody levels, cellular immune responses, and viral variants in 4 separate groups: healthy controls (HCs) weeks (early) or months (late) following vaccination in comparison with symptomatic patients with SARS-CoV-2 after partial or full mRNA vaccination. During the period of the study, most symptomatic breakthrough infections were caused by the SARS-CoV-2 Alpha variant. Neutralizing antibody levels in the HCs were sustained over time against the vaccine parent virus but decreased against the Alpha variant, whereas IgG titers and T cell responses against the parent virus and Alpha variant declined over time. Both partially and fully vaccinated patients with symptomatic infections had lower virus neutralizing antibody levels against the parent virus than the HCs, similar IgG antibody titers, and similar virus-specific T cell responses measured by IFN-γ. Compared with HCs, neutralization activity against the Alpha variant was lower in the partially vaccinated infected patients and tended to be lower in the fully vaccinated infected patients. In this cohort of breakthrough infections, parent virus neutralization was the superior predictor of breakthrough infections with the Alpha variant of SARS-CoV-2.

Purpose: Molecular imaging has provided unparalleled opportunities to monitor disease processes, although tools for evaluating infection remain limited. Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by lung injury that we sought to model. Activated macrophages/phagocytes have an important role in lung injury, which is responsible for subsequent respiratory failure and death. We performed pulmonary PET/CT with 124 I-iodo-DPA-713, a low-molecular-weight pyrazolopyrimidine ligand selectively trapped by activated macrophages cells, to evaluate the local immune response in a hamster model of SARS-CoV-2 infection., Procedures: Pulmonary 124 I-iodo-DPA-713 PET/CT was performed in SARS-CoV-2-infected golden Syrian hamsters. CT images were quantified using a custom-built lung segmentation tool. Studies with DPA-713-IRDye680LT and a fluorescent analog of DPA-713 as well as histopathology and flow cytometry were performed on post-mortem tissues., Results: Infected hamsters were imaged at the peak of inflammatory lung disease (7 days post-infection). Quantitative CT analysis was successful for all scans and demonstrated worse pulmonary disease in male versus female animals (P < 0.01). Increased 124 I-iodo-DPA-713 PET activity co-localized with the pneumonic lesions. Additionally, higher pulmonary 124 I-iodo-DPA-713 PET activity was noted in male versus female hamsters (P = 0.02). DPA-713-IRDye680LT also localized to the pneumonic lesions. Flow cytometry demonstrated a higher percentage of myeloid and CD11b + cells (macrophages, phagocytes) in male versus female lung tissues (P = 0.02)., Conclusion: 124 I-Iodo-DPA-713 accumulates within pneumonic lesions in a hamster model of SARS-CoV-2 infection. As a novel molecular imaging tool, 124 I-Iodo-DPA-713 PET could serve as a noninvasive, clinically translatable approach to monitor SARS-CoV-2-associated pulmonary inflammation and expedite the development of novel therapeutics for COVID-19., (© 2021. World Molecular Imaging Society.)

BACKGROUNDWhile most children who contract COVID-19 experience mild disease, high-risk children with underlying conditions may develop severe disease, requiring interventions. Kinetics of antibodies transferred via COVID-19 convalescent plasma early in disease have not been characterized.METHODSIn this study, high-risk children were prospectively enrolled to receive high-titer COVID-19 convalescent plasma (>1:320 anti-spike IgG; Euroimmun). Passive transfer of antibodies and endogenous antibody production were serially evaluated for up to 2 months after transfusion. Commercial and research ELISA assays, virus neutralization assays, high-throughput phage-display assay utilizing a coronavirus epitope library, and pharmacokinetic analyses were performed.RESULTSFourteen high-risk children (median age, 7.5 years) received high-titer COVID-19 convalescent plasma, 9 children within 5 days (range, 2-7 days) of symptom onset and 5 children within 4 days (range, 3-5 days) after exposure to SARS-CoV-2. There were no serious adverse events related to transfusion. Antibodies against SARS-CoV-2 were transferred from the donor to the recipient, but antibody titers declined by 14-21 days, with a 15.1-day half-life for spike protein IgG. Donor plasma had significant neutralization capacity, which was transferred to the recipient. However, as early as 30 minutes after transfusion, recipient plasma neutralization titers were 6.2% (range, 5.9%-6.7%) of donor titers.CONCLUSIONConvalescent plasma transfused to high-risk children appears to be safe, with expected antibody kinetics, regardless of weight or age. However, current use of convalescent plasma in high-risk children achieves neutralizing capacity, which may protect against severe disease but is unlikely to provide lasting protection.Trial registrationClinicalTrials.gov NCT04377672.FundingThe state of Maryland, Bloomberg Philanthropies, and the NIH (grants R01-AI153349, R01-AI145435-A1, K08-AI139371-A1, and T32-AI052071).

Background: Severe acute respiratory syndrome coronavirus 2, the disease-causing pathogen of the coronavirus disease 2019 pandemic, has resulted in morbidity and mortality worldwide. Pregnant women are more susceptible to severe coronavirus disease 2019 and are at higher risk of preterm birth than uninfected pregnant women. Despite this evidence, the immunologic effects of severe acute respiratory syndrome coronavirus 2 infection during pregnancy remain understudied., Objective: This study aimed to assess the impact of severe acute respiratory syndrome coronavirus 2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to severe acute respiratory syndrome coronavirus 2 among pregnant and nonpregnant women., Study Design: Immune responses to severe acute respiratory syndrome coronavirus 2 were analyzed using samples from pregnant (n=33) and nonpregnant (n=17) women who tested either positive (pregnant, 22; nonpregnant, 17) or negative for severe acute respiratory syndrome coronavirus 2 (pregnant, 11) at Johns Hopkins Hospital. We measured proinflammatory and placental cytokine messenger RNAs, neonatal Fc receptor expression, and tetanus antibody transfer in maternal and cord blood samples. In addition, we evaluated antispike immunoglobulin G, antispike receptor-binding domain immunoglobulin G, and neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 in serum or plasma collected from nonpregnant women, pregnant women, and cord blood., Results: Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection expressed more interleukin-1 beta, but not interleukin 6, in blood samples collected within 14 days vs >14 days after performing severe acute respiratory syndrome coronavirus 2 test. Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection also had reduced antispike receptor-binding domain immunoglobulin G titers and were less likely to have detectable neutralizing antibody than nonpregnant women. Although severe acute respiratory syndrome coronavirus 2 infection did not disrupt neonatal Fc receptor expression in the placenta, maternal transfer of severe acute respiratory syndrome coronavirus 2 neutralizing antibody was inhibited by infection during pregnancy., Conclusion: Severe acute respiratory syndrome coronavirus 2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of coronavirus disease 2019 treatment in pregnancy. In addition, the long-term implications of placental inflammation for neonatal health require greater consideration., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more severe outcomes are reported in males than in females, including hospitalizations and deaths. Animal models can provide an opportunity to mechanistically interrogate causes of sex differences in the pathogenesis of SARS-CoV-2. Adult male and female golden Syrian hamsters (8 to 10 weeks of age) were inoculated intranasally with 10 5 50% tissue culture infective dose (TCID 50 ) of SARS-CoV-2/USA-WA1/2020 and euthanized at several time points during the acute (i.e., virus actively replicating) and recovery (i.e., after the infectious virus has been cleared) phases of infection. There was no mortality, but infected male hamsters experienced greater morbidity, losing a greater percentage of body mass, developed more extensive pneumonia as noted on chest computed tomography, and recovered more slowly than females. Treatment of male hamsters with estradiol did not alter pulmonary damage. Virus titers in respiratory tissues, including nasal turbinates, trachea, and lungs, and pulmonary cytokine concentrations, including interferon-β (IFN-β) and tumor necrosis factor-α (TNF-α), were comparable between the sexes. However, during the recovery phase of infection, females mounted 2-fold greater IgM, IgG, and IgA responses against the receptor-binding domain of the spike protein (S-RBD) in both plasma and respiratory tissues. Female hamsters also had significantly greater IgG antibodies against whole-inactivated SARS-CoV-2 and mutant S-RBDs as well as virus-neutralizing antibodies in plasma. The development of an animal model to study COVID-19 sex differences will allow for a greater mechanistic understanding of the SARS-CoV-2-associated sex differences seen in the human population. IMPORTANCE Men experience more severe outcomes from coronavirus disease 2019 (COVID-19) than women. Golden Syrian hamsters were used to explore sex differences in the pathogenesis of a human isolate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After inoculation, male hamsters experienced greater sickness, developed more severe lung pathology, and recovered more slowly than females. Sex differences in disease could not be reversed by estradiol treatment in males and were not explained by either virus replication kinetics or the concentrations of inflammatory cytokines in the lungs. During the recovery period, antiviral antibody responses in the respiratory tract and plasma, including to newly emerging SARS-CoV-2 variants, were greater in female than in male hamsters. Greater lung pathology during the acute phase combined with lower antiviral antibody responses during the recovery phase of infection in males than in females illustrate the utility of golden Syrian hamsters as a model to explore sex differences in the pathogenesis of SARS-CoV-2 and vaccine-induced immunity and protection.

Multiple studies have shown loss of severe acute respiratory syndrome coronavirus 2-specific (SARS-CoV-2-specific) antibodies over time after infection, raising concern that humoral immunity against the virus is not durable. If immunity wanes quickly, millions of people may be at risk for reinfection after recovery from coronavirus disease 2019 (COVID-19). However, memory B cells (MBCs) could provide durable humoral immunity even if serum neutralizing antibody titers decline. We performed multidimensional flow cytometric analysis of S protein receptor binding domain-specific (S-RBD-specific) MBCs in cohorts of ambulatory patients with COVID-19 with mild disease (n = 7), and hospitalized patients with moderate to severe disease (n = 7), at a median of 54 days (range, 39-104 days) after symptom onset. We detected S-RBD-specific class-switched MBCs in 13 of 14 participants, failing only in the individual with the lowest plasma levels of anti-S-RBD IgG and neutralizing antibodies. Resting MBCs (rMBCs) made up the largest proportion of S-RBD-specific MBCs in both cohorts. FCRL5, a marker of functional memory on rMBCs, was more dramatically upregulated on S-RBD-specific rMBCs after mild infection than after severe infection. These data indicate that most SARS-CoV-2-infected individuals develop S-RBD-specific, class-switched rMBCs that resemble germinal center-derived B cells induced by effective vaccination against other pathogens, providing evidence for durable B cell-mediated immunity against SARS-CoV-2 after mild or severe disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic that has infected over 36 million and killed over 1 million people. Informed implementation of government public health policies depends on accurate data on SARS-CoV-2 immunity at a population scale. We hypothesized that detection of SARS-CoV-2 salivary antibodies could serve as a noninvasive alternative to serological testing for monitoring of SARS-CoV-2 infection and seropositivity at a population scale. We developed a multiplex SARS-CoV-2 antibody immunoassay based on Luminex technology that comprised 12 CoV antigens, mostly derived from SARS-CoV-2 nucleocapsid (N) and spike (S). Saliva and sera collected from confirmed coronavirus disease 2019 (COVID-19) cases and from the pre-COVID-19 era were tested for IgG, IgA, and IgM to the antigen panel. Matched saliva and serum IgG responses ( n  = 28) were significantly correlated. The salivary anti-N IgG response resulted in the highest sensitivity (100%), exhibiting a positive response in 24/24 reverse transcription-PCR (RT-PCR)-confirmed COVID-19 cases sampled at >14 days post-symptom onset (DPSO), whereas the salivary anti-receptor binding domain (RBD) IgG response yielded 100% specificity. Temporal kinetics of IgG in saliva were consistent with those observed in blood and indicated that most individuals seroconvert at around 10 DPSO. Algorithms employing a combination of the IgG responses to N and S antigens result in high diagnostic accuracy (100%) by as early as 10 DPSO. These results support the use of saliva-based antibody testing as a noninvasive and scalable alternative to blood-based antibody testing., (Copyright © 2020 American Society for Microbiology.)

In October 2020, the National Cancer Institute (NCI) Serological Sciences Network (SeroNet) was established to study the immune response to COVID-19, and "to develop, validate, improve, and implement serological testing and associated technologies" (https://www.cancer.gov/research/key-initiatives/covid-19/coronavirus-research-initiatives/serological-sciences-network). SeroNet is comprised of 25 participating research institutions partnering with the Frederick National Laboratory for Cancer Research (FNLCR) and the SeroNet Coordinating Center. Since its inception, SeroNet has supported collaborative development and sharing of COVID-19 serological assay procedures and has set forth plans for assay harmonization. To facilitate collaboration and procedure sharing, a detailed survey was sent to collate comprehensive assay details and performance metrics on COVID-19 serological assays within SeroNet. In addition, FNLCR established a protocol to calibrate SeroNet serological assays to reference standards, such as the U.S. severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology standard reference material and first WHO international standard (IS) for anti-SARS-CoV-2 immunoglobulin (20/136), to facilitate harmonization of assay reporting units and cross-comparison of study data. SeroNet institutions reported development of a total of 27 enzyme-linked immunosorbent assay (ELISA) methods, 13 multiplex assays, and 9 neutralization assays and use of 12 different commercial serological methods. FNLCR developed a standardized protocol for SeroNet institutions to calibrate these diverse serological assays to reference standards. In conclusion, SeroNet institutions have established a diverse array of COVID-19 serological assays to study the immune response to SARS-CoV-2 and vaccines. Calibration of SeroNet serological assays to harmonize results reporting will facilitate future pooled data analyses and study cross-comparisons. IMPORTANCE SeroNet institutions have developed or implemented 61 diverse COVID-19 serological assays and are collaboratively working to harmonize these assays using reference materials to establish standardized reporting units. This will facilitate clinical interpretation of serology results and cross-comparison of research data.

BackgroundGlobal efforts are needed to elucidate the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the underlying cause of coronavirus disease 2019 (COVID-19), including seroprevalence, risk factors, and long-term sequelae, as well as immune responses after vaccination across populations and the social dimensions of prevention and treatment strategies.MethodsIn the United States, the National Cancer Institute in partnership with the National Institute of Allergy and Infectious Diseases, established the SARS-CoV-2 Serological Sciences Network (SeroNet) as the nation's largest coordinated effort to study coronavirus disease 2019. The network comprises multidisciplinary researchers bridging gaps and fostering collaborations among immunologists, epidemiologists, virologists, clinicians and clinical laboratories, social and behavioral scientists, policymakers, data scientists, and community members. In total, 49 institutions form the SeroNet consortium to study individuals with cancer, autoimmune disease, inflammatory bowel diseases, cardiovascular diseases, human immunodeficiency virus, transplant recipients, as well as otherwise healthy pregnant women, children, college students, and high-risk occupational workers (including healthcare workers and first responders).ResultsSeveral studies focus on underrepresented populations, including ethnic minorities and rural communities. To support integrative data analyses across SeroNet studies, efforts are underway to define common data elements for standardized serology measurements, cellular and molecular assays, self-reported data, treatment, and clinical outcomes.ConclusionsIn this paper, we discuss the overarching framework for SeroNet epidemiology studies, critical research questions under investigation, and data accessibility for the worldwide scientific community. Lessons learned will help inform preparedness and responsiveness to future emerging diseases.

Severe outcomes and death from the novel coronavirus disease 2019 (COVID-19) appear to be characterized by an exaggerated immune response with hypercytokinemia leading to inflammatory infiltration of the lungs and acute respiratory distress syndrome. Risk of severe COVID-19 outcomes is consistently lower in women than men worldwide, suggesting that female biological sex is instrumental in protection. This mini-review discusses the immunomodulatory and anti-inflammatory actions of high physiological concentrations of the steroids 17β-estradiol (E2) and progesterone (P4). We review how E2 and P4 favor a state of decreased innate immune inflammatory response while enhancing immune tolerance and antibody production. We discuss how the combination of E2 and P4 may improve the immune dysregulation that leads to the COVID-19 cytokine storm. It is intended to stimulate novel consideration of the biological forces that are protective in women compared to men, and to therapeutically harness these factors to mitigate COVID-19 morbidity and mortality.

Antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination are reduced in solid organ transplant recipients (SOTRs). We report that increased levels of preexisting antibodies to seasonal coronaviruses are associated with decreased antibody response to SARS-CoV-2 vaccination in SOTRs, supporting that antigenic imprinting modulates vaccine responses in SOTRs. [ABSTRACT FROM AUTHOR]

Several vaccines have been introduced to combat the coronavirus infectious disease‐2019 (COVID‐19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Current SARS‐CoV‐2 vaccines include mRNA‐containing lipid nanoparticles or adenoviral vectors that encode the SARS‐CoV‐2 Spike (S) protein of SARS‐CoV‐2, inactivated virus, or protein subunits. Despite growing success in worldwide vaccination efforts, additional capabilities may be needed in the future to address issues such as stability and storage requirements, need for vaccine boosters, desirability of different routes of administration, and emergence of SARS‐CoV‐2 variants such as the Delta variant. Here, we present a novel, well‐characterized SARS‐CoV‐2 vaccine candidate based on extracellular vesicles (EVs) of Salmonella typhimurium that are decorated with the mammalian cell culture‐derived Spike receptor‐binding domain (RBD). RBD‐conjugated outer membrane vesicles (RBD‐OMVs) were used to immunize the golden Syrian hamster (Mesocricetus auratus) model of COVID‐19. Intranasal immunization resulted in high titres of blood anti‐RBD IgG as well as detectable mucosal responses. Neutralizing antibody activity against wild‐type and Delta variants was evident in all vaccinated subjects. Upon challenge with live virus, hamsters immunized with RBD‐OMV, but not animals immunized with unconjugated OMVs or a vehicle control, avoided body mass loss, had lower virus titres in bronchoalveolar lavage fluid, and experienced less severe lung pathology. Our results emphasize the value and versatility of OMV‐based vaccine approaches. [ABSTRACT FROM AUTHOR]

Purpose: Molecular imaging has provided unparalleled opportunities to monitor disease processes, although tools for evaluating infection remain limited. Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by lung injury that we sought to model. Activated macrophages/phagocytes have an important role in lung injury, which is responsible for subsequent respiratory failure and death. We performed pulmonary PET/CT with 124I-iodo-DPA-713, a low-molecular-weight pyrazolopyrimidine ligand selectively trapped by activated macrophages cells, to evaluate the local immune response in a hamster model of SARS-CoV-2 infection. Procedures: Pulmonary 124I-iodo-DPA-713 PET/CT was performed in SARS-CoV-2-infected golden Syrian hamsters. CT images were quantified using a custom-built lung segmentation tool. Studies with DPA-713-IRDye680LT and a fluorescent analog of DPA-713 as well as histopathology and flow cytometry were performed on post-mortem tissues. Results: Infected hamsters were imaged at the peak of inflammatory lung disease (7 days post-infection). Quantitative CT analysis was successful for all scans and demonstrated worse pulmonary disease in male versus female animals (P < 0.01). Increased 124I-iodo-DPA-713 PET activity co-localized with the pneumonic lesions. Additionally, higher pulmonary 124I-iodo-DPA-713 PET activity was noted in male versus female hamsters (P = 0.02). DPA-713-IRDye680LT also localized to the pneumonic lesions. Flow cytometry demonstrated a higher percentage of myeloid and CD11b + cells (macrophages, phagocytes) in male versus female lung tissues (P = 0.02). Conclusion: 124I-Iodo-DPA-713 accumulates within pneumonic lesions in a hamster model of SARS-CoV-2 infection. As a novel molecular imaging tool, 124I-Iodo-DPA-713 PET could serve as a noninvasive, clinically translatable approach to monitor SARS-CoV-2-associated pulmonary inflammation and expedite the development of novel therapeutics for COVID-19. [ABSTRACT FROM AUTHOR]

The ongoing COVID-19 pandemic has increased awareness about sex-specific differences in immunity and outcomes following SARS-CoV-2 infection. Strong evidence of a male bias in COVID-19 disease severity is hypothesized to be mediated by sex differential immune responses against SARS-CoV-2. This hypothesis is based on data from other viral infections, including influenza viruses, HIV, hepatitis viruses, and others that have demonstrated sex-specific immunity to viral infections. Although males are more susceptible to most viral infections, females possess immunological features that render them more vulnerable to distinct immune-related disease outcomes. Both sex chromosome complement and related genes as well as sex steroids play important roles in mediating the development of sex differences in immunity to viral infections. [ABSTRACT FROM AUTHOR]

The current novel coronavirus disease 2019 (COVID-19) pandemic is revealing profound differences between men and women in disease outcomes worldwide. In the United States, there has been inconsistent reporting and analyses of male–female differences in COVID-19 cases, hospitalizations, and deaths. We seek to raise awareness about the male-biased severe outcomes from COVID-19, highlighting the mechanistic differences including in the expression and activity of angiotensin-converting enzyme 2 (ACE2) as well as in antiviral immunity. We also highlight how sex differences in comorbidities, which can be associated with both age and race, impact male-biased outcomes from COVID-19. [ABSTRACT FROM AUTHOR]

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic was first reported in Wuhan, China in December 2019, moved across the globe at an unprecedented speed, and is having a profound and yet still unfolding health and socioeconomic impacts. SARS-CoV-2, a β-coronavirus, is a highly contagious respiratory pathogen that causes a disease that has been termed the 2019 coronavirus disease (COVID-19). Clinical experience thus far indicates that COVID-19 is highly heterogeneous, ranging from being asymptomatic and mild to severe and causing death. Host factors including age, sex, and comorbid conditions are key determinants of disease severity and progression. Aging itself is a prominent risk factor for severe disease and death from COVID-19. We hypothesize that age-related decline and dysregulation of immune function, i.e., immunosenescence and inflammaging play a major role in contributing to heightened vulnerability to severe COVID-19 outcomes in older adults. Much remains to be learned about the immune responses to SARS-CoV-2 infection. We need to begin partitioning all immunological outcome data by age to better understand disease heterogeneity and aging. Such knowledge is critical not only for understanding of COVID-19 pathogenesis but also for COVID-19 vaccine development. [ABSTRACT FROM AUTHOR]

Males are disproportionately affected by severe disease and death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In their recent article, Takahashi et al. found sex differences in immune responses to SARS-CoV-2 and the predictors of disease progression. These findings contribute to elucidating the mechanisms that underlie the male bias in severe disease and death from coronavirus disease 2019 (COVID-19). [ABSTRACT FROM AUTHOR]

• Vaccinated older adults were categorized as eager or hesitant compliers (HC). • More of the Black participants, particularly women, were characterized as HC. • HC perceived risks associated with the vaccines and the system providing them. • Sources of hesitation and promoters of vaccination were shaped by race and gender. COVID-19 vaccines are essential public health tools for protecting older adults, who are at high risk of severe outcomes associated with COVID-19. Little is known, however, about how older adults approach the decision to receive a COVID-19 vaccine. We hypothesized that intersections between gender and race may provide unique insight into the decision-making process and the factors that lead to vaccine uptake among hesitant individuals. We performed in-depth interviews with 24 older adults who had been vaccinated against COVID-19 and used the framework approach with an intersectional lens to analyze data. Two typologies emerged: eager compliers did not question the need to vaccinate, whereas hesitant compliers were skeptical of the vaccine and underwent a thorough decision-making process prior to vaccination. For eager compliers, the vaccine offered protection from a disease that posed a serious threat, and few risks were perceived. In contrast, hesitant compliers perceived risks associated with the vaccine product or mistrusted the infrastructure that led to rapid vaccine development. Hesitancy was greater among Black participants, and only Black participants reported mistrust in vaccine infrastructure. At the intersection of gender and race, a 'White male effect' was observed, whereby White men perceived the fewest risks associated with the vaccine, and Black women were the most fearful of serious side effects. Nearly all hesitant compliers ultimately got vaccinated due to the threat of COVID-19. Convenient access through vaccine clinics in senior's buildings was pivotal for hesitant compliers and external and internal influences had differential impacts by race and gender. Emphasizing the risk of COVID-19, convenient and accessible opportunities for vaccination, and messages that are targeted to specific groups are likely to increase vaccine uptake among older adults. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) continues to exact a devastating global toll. Ascertaining the factors underlying differential susceptibility and prognosis following viral exposure is critical to improving public health responses. We propose that gut microbes may contribute to variation in COVID-19 outcomes. We synthesise evidence for gut microbial contributions to immunity and inflammation, and associations with demographic factors affecting disease severity. We suggest mechanisms potentially underlying microbially mediated differential susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These include gut microbiome-mediated priming of host inflammatory responses and regulation of endocrine signalling, with consequences for the cellular features exploited by SARS-CoV-2 virions. We argue that considering gut microbiome-mediated mechanisms may offer a lens for appreciating differential susceptibility to SARS-CoV-2, potentially contributing to clinical and epidemiological approaches to understanding and managing COVID-19. The outcomes of SARS-CoV-2 infection and COVID-19 show enormous variation among individuals. Given that the sources of this variation are largely unknown, they have been described as 'immunological dark matter'. Emerging studies suggest that the gut microbiome contributes to immunological dark matter. Gut microbial composition and function are associated with several key risk factors for severe COVID-19 outcomes, including host inflammatory status, age, and biological sex. Crucially, the gut microbiome regulates host inflammation and endocrine function in ways that may alter susceptibility to SARS-CoV-2 infection. Efforts to study the gut microbiome alongside other host demographic and physiological variables may shed light on differential susceptibility to SARS-CoV-2 infection, and may thereby contribute to improving patient care and epidemiological modelling. [ABSTRACT FROM AUTHOR]

Oral fluid (hereafter, saliva) is a non-invasive and attractive alternative to blood for SARS-CoV-2 IgG testing; however, the heterogeneity of saliva as a matrix poses challenges for immunoassay performance. To optimize performance of a magnetic microparticle-based multiplex immunoassay (MIA) for SARS-CoV-2 IgG measurement in saliva, with consideration of: i) threshold setting and validation across different MIA bead batches; ii) sample qualification based on salivary total IgG concentration; iii) calibration to U.S. SARS-CoV-2 serological standard binding antibody units (BAU); and iv) correlations with blood-based SARS-CoV-2 serological and neutralizing antibody (nAb) assays. The salivary SARS-CoV-2 IgG MIA included 2 nucleocapsid (N), 3 receptor-binding domain (RBD), and 2 spike protein (S) antigens. Gingival crevicular fluid (GCF) swab saliva samples were collected before December 2019 (n = 555) and after molecular test-confirmed SARS-CoV-2 infection from 113 individuals (providing up to 5 repeated-measures; n = 398) and used to optimize and validate MIA performance (total n = 953). Combinations of IgG responses to N, RBD and S and total salivary IgG concentration (μg/mL) as a qualifier of nonreactive samples were optimized and validated, calibrated to the U.S. SARS-CoV-2 serological standard, and correlated with blood-based SARS-CoV-2 IgG ELISA and nAb assays. The sum of signal to cutoff (S/Co) to all seven MIA SARS-CoV-2 antigens and disqualification of nonreactive saliva samples with ≤15 μg/mL total IgG led to correct classification of 62/62 positives (sensitivity [Se] = 100.0%; 95% confidence interval [CI] = 94.8%, 100.0%) and 108/109 negatives (specificity [Sp] = 99.1%; 95% CI = 97.3%, 100.0%) at 8-million beads coupling scale and 80/81 positives (Se = 98.8%; 95% CI = 93.3%, 100.0%] and 127/127 negatives (Sp = 100%; 95% CI = 97.1%, 100.0%) at 20-million beads coupling scale. Salivary SARS-CoV-2 IgG crossed the MIA cutoff of 0.1 BAU/mL on average 9 days post-COVID-19 symptom onset and peaked around day 30. Among n = 30 matched saliva and plasma samples, salivary SARS-CoV-2 MIA IgG levels correlated with corresponding-antigen plasma ELISA IgG (N: ρ = 0.76, RBD: ρ = 0.83, S: ρ = 0.82; all p < 0.001). Correlations of plasma SARS-CoV-2 nAb assay area under the curve (AUC) with salivary MIA IgG (N: ρ = 0.68, RBD: ρ = 0.78, S: ρ = 0.79; all p < 0.001) and with plasma ELISA IgG (N: ρ = 0.76, RBD: ρ = 0.79, S: ρ = 0.76; p < 0.001) were similar. A salivary SARS-CoV-2 IgG MIA produced consistently high Se (> 98.8%) and Sp (> 99.1%) across two bead coupling scales and correlations with nAb responses that were similar to blood-based SARS-CoV-2 IgG ELISA data. This non-invasive salivary SARS-CoV-2 IgG MIA could increase engagement of vulnerable populations and improve broad understanding of humoral immunity (kinetics and gaps) within the evolving context of booster vaccination, viral variants and waning immunity. [Display omitted] • A multiplex SARS-CoV-2 IgG immunoassay for oral fluid (saliva) was developed. • Variability in oral fluid as sample matrix poses challenges for assay performance. • Salivary total IgG concentration as sample qualifier greatly improves assay performance. • Non-invasive self-collection of oral fluid overcomes repeated blood draw barriers. • High accuracy oral fluid assays ideally suited to study antibody kinetics, waning, mucosal response. [ABSTRACT FROM AUTHOR]