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1.
Front Aging ; 3: 836642, 2022.
Article in English | MEDLINE | ID: covidwho-1933924

ABSTRACT

Sex differences in the immune system are dynamic throughout the lifespan and contribute to heterogeneity in the risk of infectious diseases and the response to vaccination in older adults. The importance of the intersection between sex and age in immunity to viral respiratory diseases is clearly demonstrated by the increased prevalence and severity of influenza and COVID-19 in older males compared to older females. Despite sex and age biases in the epidemiology and clinical manifestations of disease, these host factors are often ignored in vaccine research. Here, we review sex differences in the immunogenicity, effectiveness, and safety of the influenza and COVID-19 vaccines in older adults and the impact of sex-specific effects of age-related factors, including chronological age, frailty, and the presence of comorbidities. While a female bias in immunity to influenza vaccines has been consistently reported, understanding of sex differences in the response to COVID-19 vaccines in older adults is incomplete due to small sample sizes and failure to disaggregate clinical trial data by both sex and age. For both vaccines, a major gap in the literature is apparent, whereby very few studies investigate sex-specific effects of aging, frailty, or multimorbidity. By providing a roadmap for sex-responsive vaccine research, beyond influenza and COVID-19, we can leverage the heterogeneity in immunity among older adults to provide better protection against vaccine-preventable diseases.

2.
Immunol Rev ; 309(1): 86-89, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1901688

ABSTRACT

After more than 20 years of studying sex differences in viral pathogenesis and immunity to vaccines, the COVID-19 pandemic provided me with a unique opportunity to raise awareness about biological sex differences. The scientific community and public, alike, embraced the clinical and epidemiological data and supported inquiries into how males are twice as likely to be hospitalized and die from COVID-19. Immunological changes associated with pregnancy also contribute to worse outcomes from COVID-19. Collectively, we are finding that inflammation is a critical mediator of worse outcomes for males and pregnant females. The pandemic gave me a platform to discuss and address sex differences on a bigger stage, but two decades of studies working with other viruses prepared me for this moment in history.


Subject(s)
COVID-19 , Pandemics , COVID-19/epidemiology , Female , Humans , Male , Pregnancy , Women's Health
3.
mSphere ; : e0019322, 2022 Jun 15.
Article in English | MEDLINE | ID: covidwho-1891742

ABSTRACT

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.

4.
Clin Infect Dis ; 2022 May 24.
Article in English | MEDLINE | ID: covidwho-1860834

ABSTRACT

BACKGROUND: Male sex and old age are risk factors for severe COVID-19, but the intersection of sex and aging on antibody responses to SARS-CoV-2 vaccines has not been characterized. METHODS: Plasma samples were collected from older adults (75-98 years) before and after three doses of SARS-CoV-2 mRNA vaccination, and from younger adults (18-74 years) post-dose two, for comparison. Antibody binding to SARS-CoV-2 antigens (spike protein [S], S-receptor binding domain [S-RBD], and nucleocapsid [N]), functional activity against S, and live-virus neutralization were measured against the vaccine virus and the Alpha, Delta, and Omicron variants of concern (VOC). RESULTS: Vaccination induced greater antibody titers in older females than males, with both age and frailty associated with reduced antibody responses in males, but not females. Responses declined significantly in the six months following the second dose. The third dose restored functional antibody responses and eliminated disparities caused by sex, age, and frailty in older adults. Responses to the VOCs, particularly the Omicron variant, were significantly reduced relative to the vaccine virus, with older males having lower titers to the VOCs than females. Older adults had lower responses to the vaccine and VOC viruses than younger adults, with disparities being greater in males than females. CONCLUSION: Older and frail males may be more vulnerable to breakthrough infections due to low antibody responses before receipt of a third vaccine dose. Promoting third dose coverage in older adults, especially males, is crucial to protecting this vulnerable population.

5.
Nat Rev Immunol ; 20(7): 442-447, 2020 07.
Article in English | MEDLINE | ID: covidwho-1830064

ABSTRACT

A male bias in mortality has emerged in the COVID-19 pandemic, which is consistent with the pathogenesis of other viral infections. Biological sex differences may manifest themselves in susceptibility to infection, early pathogenesis, innate viral control, adaptive immune responses or the balance of inflammation and tissue repair in the resolution of infection. We discuss available sex-disaggregated epidemiological data from the COVID-19 pandemic, introduce sex-differential features of immunity and highlight potential sex differences underlying COVID-19 severity. We propose that sex differences in immunopathogenesis will inform mechanisms of COVID-19, identify points for therapeutic intervention and improve vaccine design and increase vaccine efficacy.


Subject(s)
Coronavirus Infections/epidemiology , Pneumonia, Viral/epidemiology , Adaptive Immunity , Age Factors , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Female , Humans , Interferons/immunology , Male , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , SARS-CoV-2 , Severity of Illness Index , Sex Factors , Sociological Factors
6.
Transplantation ; 106(7): 1440-1444, 2022 07 01.
Article in English | MEDLINE | ID: covidwho-1788574

ABSTRACT

BACKGROUND: Humoral responses to coronavirus disease 2019 (COVID-19) vaccines are attenuated in solid organ transplant recipients (SOTRs), necessitating additional booster vaccinations. The Omicron variant demonstrates substantial immune evasion, and it is unknown whether additional vaccine doses increase neutralizing capacity versus this variant of concern (VOC) among SOTRs. METHODS: Within an observational cohort, 25 SOTRs with low seroresponse underwent anti-severe acute respiratory syndrome coronavirus 2 spike and receptor-binding domain immunoglobulin (Ig)G testing using a commercially available multiplex ELISA before and after a fourth COVID-19 vaccine dose (D4). Surrogate neutralization (percent angiotensin-converting enzyme 2 inhibition [%ACE2i], range 0%-100% with >20% correlating with live virus neutralization) was measured against full-length spike proteins of the vaccine strain and 5 VOCs including Delta and Omicron. Changes in IgG level and %ACE2i were compared using the paired Wilcoxon signed-rank test. RESULTS: Anti-receptor-binding domain and anti-spike seropositivity increased post-D4 from 56% to 84% and 68% to 88%, respectively. Median (interquartile range) anti-spike antibody significantly increased post-D4 from 42.3 (4.9-134.2) to 228.9 (1115.4-655.8) World Health Organization binding antibody units. %ACE2i (median [interquartile range]) also significantly increased against the vaccine strain (5.8% [0%-16.8%] to 20.6% [5.8%-45.9%]) and the Delta variant (9.1% [4.9%-12.8%] to 17.1% [10.3%-31.7%]), yet neutralization versus Omicron was poor, did not increase post-D4 (4.1% [0%-6.9%] to 0.5% [0%-5.7%]), and was significantly lower than boosted healthy controls. CONCLUSIONS: Although a fourth vaccine dose increases anti-spike IgG and neutralizing capacity against many VOCs, some SOTRs may remain at high risk for Omicron infection despite boosting. Thus, additional protective interventions or alternative vaccination strategies should be urgently explored.


Subject(s)
COVID-19 Vaccines , COVID-19 , Immunization, Secondary , Transplant Recipients , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Immunoglobulin G/blood , SARS-CoV-2
7.
J Extracell Vesicles ; 11(3): e12192, 2022 03.
Article in English | MEDLINE | ID: covidwho-1739175

ABSTRACT

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.


Subject(s)
COVID-19 , Extracellular Vesicles , Viral Vaccines , Animals , Antibodies, Neutralizing , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Liposomes , Mammals , Nanoparticles , SARS-CoV-2
8.
Vaccine ; 40(11): 1643-1654, 2022 03 08.
Article in English | MEDLINE | ID: covidwho-1713020

ABSTRACT

BACKGROUND: Influenza is a significant threat to public health worldwide. Despite the widespread availability of effective and generally safe vaccines, the acceptance and coverage of influenza vaccines are significantly lower than recommended. Sociodemographic variables are known to be potential predictors of differential influenza vaccine uptake and outcomes. OBJECTIVES: This review aims to (1) identify how sociodemographic characteristics such as age, sex, gender, and race may influence seasonal influenza vaccine acceptance and coverage; and (2) evaluate the role of these sociodemographic characteristics in differential adverse reactions among vaccinated individuals. METHODS: PubMed was used as the database to search for published literature in three thematic areas related to the seasonal influenza vaccine - vaccine acceptance, adverse reactions, and vaccine coverage. RESULTS: A total of 3249 articles published between 2010 and 2020 were screened and reviewed, of which 39 studies were included in this literature review. By the three thematic areas, 17 studies assessed vaccine acceptance, 8 studies focused on adverse reactions, and 14 examined coverage of the seasonal influenza vaccine. There were also two studies that focused on more than one of the areas of interest. CONCLUSION: Each of the four sociodemographic predictors - age, sex, race, and gender - were found to significantly influence vaccine acceptance, receipt and outcomes in this review.


Subject(s)
Influenza Vaccines , Influenza, Human , Humans , Influenza Vaccines/adverse effects , Influenza, Human/prevention & control , Seasons , Vaccination/adverse effects
9.
Am J Pathol ; 192(2): 195-207, 2022 02.
Article in English | MEDLINE | ID: covidwho-1703223

ABSTRACT

To catalyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research, including development of novel interventive and preventive strategies, the progression of disease was characterized in a robust coronavirus disease 2019 (COVID-19) animal model. In this model, male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 USA-WA1/2020. Groups of inoculated and mock-inoculated uninfected control animals were euthanized at 2, 4, 7, 14, and 28 days after inoculation to track multiple clinical, pathology, virology, and immunology outcomes. SARS-CoV-2-inoculated animals consistently lost body weight during the first week of infection, had higher lung weights at terminal time points, and developed lung consolidation per histopathology and quantitative image analysis measurements. High levels of infectious virus and viral RNA were reliably present in the respiratory tract at days 2 and 4 after inoculation, corresponding with widespread necrosis and inflammation. At day 7, when the presence of infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses (type II hyperplasia) dominated in the lung. These lesions resolved over time, with only residual epithelial repair evident by day 28 after inoculation. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19 using the hamster COVID-19 model.


Subject(s)
COVID-19/pathology , Animals , COVID-19/virology , Cricetinae , Disease Models, Animal , Female , Lung/pathology , Male , Mesocricetus , SARS-CoV-2
10.
Am J Pathol ; 192(2): 195-207, 2022 02.
Article in English | MEDLINE | ID: covidwho-1670134

ABSTRACT

To catalyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research, including development of novel interventive and preventive strategies, the progression of disease was characterized in a robust coronavirus disease 2019 (COVID-19) animal model. In this model, male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 USA-WA1/2020. Groups of inoculated and mock-inoculated uninfected control animals were euthanized at 2, 4, 7, 14, and 28 days after inoculation to track multiple clinical, pathology, virology, and immunology outcomes. SARS-CoV-2-inoculated animals consistently lost body weight during the first week of infection, had higher lung weights at terminal time points, and developed lung consolidation per histopathology and quantitative image analysis measurements. High levels of infectious virus and viral RNA were reliably present in the respiratory tract at days 2 and 4 after inoculation, corresponding with widespread necrosis and inflammation. At day 7, when the presence of infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses (type II hyperplasia) dominated in the lung. These lesions resolved over time, with only residual epithelial repair evident by day 28 after inoculation. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19 using the hamster COVID-19 model.


Subject(s)
COVID-19/pathology , Animals , COVID-19/virology , Cricetinae , Disease Models, Animal , Female , Lung/pathology , Male , Mesocricetus , SARS-CoV-2
11.
JCI Insight ; 7(5)2022 03 08.
Article in English | MEDLINE | ID: covidwho-1662370

ABSTRACT

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.


Subject(s)
Adaptive Immunity , Antibodies, Viral/immunology , COVID-19 Vaccines/pharmacology , COVID-19/virology , SARS-CoV-2/immunology , Vaccination/methods , Vaccines, Synthetic/pharmacology , /pharmacology , Adult , Aged , COVID-19/epidemiology , COVID-19/prevention & control , Female , Follow-Up Studies , Humans , Male , Middle Aged , Pandemics , Population Surveillance , Retrospective Studies , United States/epidemiology , Young Adult
12.
Am J Transplant ; 22(4): 1253-1260, 2022 04.
Article in English | MEDLINE | ID: covidwho-1583700

ABSTRACT

Vaccine-induced SARS-CoV-2 antibody responses are attenuated in solid organ transplant recipients (SOTRs) and breakthrough infections are more common. Additional SARS-CoV-2 vaccine doses increase anti-spike IgG in some SOTRs, but it is uncertain whether neutralization of variants of concern (VOCs) is enhanced. We tested 47 SOTRs for clinical and research anti-spike IgG, pseudoneutralization (ACE2 blocking), and live-virus neutralization (nAb) against VOCs before and after a third SARS-CoV-2 vaccine dose (70% mRNA, 30% Ad26.COV2.S) with comparison to 15 healthy controls after two mRNA vaccine doses. We used correlation analysis to compare anti-spike IgG assays and focused on thresholds associated with neutralization. A third SARS-CoV-2 vaccine dose increased median total anti-spike (1.6-fold), pseudoneutralization against VOCs (2.5-fold vs. Delta), and neutralizing antibodies (1.4-fold against Delta). However, neutralization activity was significantly lower than healthy controls (p < .001); 32% of SOTRs had zero detectable nAb against Delta after third vaccination compared to 100% for controls. Correlation with nAb was seen at anti-spike IgG >4 Log10 (AU/ml) on the Euroimmun ELISA and >4 Log10 (AU/ml) on the MSD research assay. These findings highlight benefits of a third vaccine dose for some SOTRs and the need for alternative strategies to improve protection in a significant subset of this population.


Subject(s)
COVID-19 , Organ Transplantation , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Organ Transplantation/adverse effects , SARS-CoV-2 , Transplant Recipients , Vaccines, Synthetic
13.
JCI Insight ; 7(2)2022 01 25.
Article in English | MEDLINE | ID: covidwho-1546626

ABSTRACT

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).


Subject(s)
Antibodies, Neutralizing/administration & dosage , Antibodies, Viral/administration & dosage , COVID-19/therapy , Pharmacokinetics , SARS-CoV-2/metabolism , Adolescent , COVID-19/blood , Child , Child, Preschool , Female , Humans , Immunization, Passive , Infant , Male , Risk Factors
14.
Trends Mol Med ; 27(12): 1115-1134, 2021 12.
Article in English | MEDLINE | ID: covidwho-1514237

ABSTRACT

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.


Subject(s)
Biomarkers/metabolism , COVID-19/microbiology , COVID-19/pathology , Gastrointestinal Microbiome/physiology , Animals , COVID-19/virology , Humans , Inflammation/microbiology , Inflammation/pathology , Inflammation/virology , SARS-CoV-2/pathogenicity , Severity of Illness Index
15.
Open Forum Infect Dis ; 8(9): ofab448, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1443088

ABSTRACT

BACKGROUND: Males experience increased severity of illness and mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared with females, but the mechanisms of male susceptibility are unclear. METHODS: We performed a retrospective cohort analysis of SARS-CoV-2 testing and admission data at 5 hospitals in the Maryland/Washington DC area. Using age-stratified logistic regression models, we quantified the impact of male sex on the risk of the composite outcome of severe disease or death (World Health Organization score 5-8) and tested the impact of demographics, comorbidities, health behaviors, and laboratory inflammatory markers on the sex effect. RESULTS: Among 213 175 SARS-CoV-2 tests, despite similar positivity rates, males in age strata between 18 and 74 years were more frequently hospitalized. For the 2626 hospitalized individuals, clinical inflammatory markers (interleukin-6, C-reactive protein, ferritin, absolute lymphocyte count, and neutrophil:lymphocyte ratio) were more favorable for females than males (P < .001). Among 18-49-year-olds, male sex carried a higher risk of severe outcomes, both early (odds ratio [OR], 3.01; 95% CI, 1.75 to 5.18) and at peak illness during hospitalization (OR, 2.58; 95% CI, 1.78 to 3.74). Despite multiple differences in demographics, presentation features, comorbidities, and health behaviors, these variables did not change the association of male sex with severe disease. Only clinical inflammatory marker values modified the sex effect, reducing the OR for severe outcomes in males aged 18-49 years to 1.81 (95% CI, 1.00 to 3.26) early and 1.39 (95% CI, 0.93 to 2.08) at peak illness. CONCLUSIONS: Higher inflammatory laboratory test values were associated with increased risk of severe coronavirus disease 2019 for males. A sex-specific inflammatory response to SARS-CoV-2 infection may underlie the sex differences in outcomes.

16.
Front Immunol ; 12: 720952, 2021.
Article in English | MEDLINE | ID: covidwho-1417084

ABSTRACT

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.


Subject(s)
COVID-19/pathology , Severity of Illness Index , Sex Characteristics , CD4 Lymphocyte Count , CD4-CD8 Ratio , Cytokines/blood , Female , Humans , Immunity, Innate/genetics , Immunity, Innate/immunology , Male , SARS-CoV-2/immunology , Sex Factors
17.
Mol Imaging Biol ; 24(1): 135-143, 2022 02.
Article in English | MEDLINE | ID: covidwho-1372811

ABSTRACT

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.


Subject(s)
Acetamides/chemistry , COVID-19/diagnostic imaging , COVID-19/veterinary , Iodine Radioisotopes/chemistry , Positron-Emission Tomography , Pyrazoles/chemistry , Pyrimidines/chemistry , SARS-CoV-2/physiology , Animals , Chlorocebus aethiops , Cricetinae , Disease Models, Animal , Lung/diagnostic imaging , Lung/pathology , Lung/virology , Positron Emission Tomography Computed Tomography , Vero Cells
18.
BMJ Glob Health ; 6(4)2021 04.
Article in English | MEDLINE | ID: covidwho-1309829
19.
mBio ; 12(4): e0097421, 2021 08 31.
Article in English | MEDLINE | ID: covidwho-1307876

ABSTRACT

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 105 50% tissue culture infective dose (TCID50) 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-ß (IFN-ß) 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.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Lung/pathology , SARS-CoV-2/immunology , Severity of Illness Index , Animals , Antibody Formation/immunology , Cricetinae , Disease Models, Animal , Estradiol/pharmacology , Female , Immunoglobulin A/blood , Immunoglobulin G/blood , Immunoglobulin M/blood , Interferon-beta/analysis , Lung/diagnostic imaging , Lung/virology , Male , Sex Factors , Spike Glycoprotein, Coronavirus/immunology , Tumor Necrosis Factor-alpha/analysis , Viral Load
20.
Front Sociol ; 6: 650729, 2021.
Article in English | MEDLINE | ID: covidwho-1295733

ABSTRACT

Epidemics and pandemics, like COVID-19, are not gender neutral. Much of the current work on gender, sex, and COVID-19, however, has seemed implicitly or explicitly to be attempting to demonstrate that either men or women have been hardest hit, treating differences between women and men as though it is not important to understand how each group is affected by the virus. This approach often leaves out the effect on gender and sexual minorities entirely. Believing that a more nuanced approach is needed now and for the future, we brought together a group of gender experts to answer the question: how are people of different genders impacted by COVID-19 and why? Individuals working in women's, men's, and LGBTQ health and wellbeing wrote sections to lay out the different ways that women, men, and gender and sexual minorities are affected by COVID-19. We demonstrate that there is not one group "most affected," but that many groups are affected, and we need to move beyond a zero-sum game and engage in ways to mutually identify and support marginalized groups.

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