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1.
Cell ; 186(6): 1263-1278.e20, 2023 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-36868218

RESUMEN

A major challenge in understanding SARS-CoV-2 evolution is interpreting the antigenic and functional effects of emerging mutations in the viral spike protein. Here, we describe a deep mutational scanning platform based on non-replicative pseudotyped lentiviruses that directly quantifies how large numbers of spike mutations impact antibody neutralization and pseudovirus infection. We apply this platform to produce libraries of the Omicron BA.1 and Delta spikes. These libraries each contain ∼7,000 distinct amino acid mutations in the context of up to ∼135,000 unique mutation combinations. We use these libraries to map escape mutations from neutralizing antibodies targeting the receptor-binding domain, N-terminal domain, and S2 subunit of spike. Overall, this work establishes a high-throughput and safe approach to measure how ∼105 combinations of mutations affect antibody neutralization and spike-mediated infection. Notably, the platform described here can be extended to the entry proteins of many other viruses.


Asunto(s)
COVID-19 , Virus ARN , Humanos , SARS-CoV-2/genética , Mutación , Anticuerpos Neutralizantes , Anticuerpos Antivirales
2.
Cell ; 185(9): 1588-1601.e14, 2022 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-35413241

RESUMEN

Immune memory is tailored by cues that lymphocytes perceive during priming. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic created a situation in which nascent memory could be tracked through additional antigen exposures. Both SARS-CoV-2 infection and vaccination induce multifaceted, functional immune memory, but together, they engender improved protection from disease, termed hybrid immunity. We therefore investigated how vaccine-induced memory is shaped by previous infection. We found that following vaccination, previously infected individuals generated more SARS-CoV-2 RBD-specific memory B cells and variant-neutralizing antibodies and a distinct population of IFN-γ and IL-10-expressing memory SARS-CoV-2 spike-specific CD4+ T cells than previously naive individuals. Although additional vaccination could increase humoral memory in previously naive individuals, it did not recapitulate the distinct CD4+ T cell cytokine profile observed in previously infected subjects. Thus, imprinted features of SARS-CoV-2-specific memory lymphocytes define hybrid immunity.


Asunto(s)
Vacunas contra la COVID-19/inmunología , COVID-19 , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/inmunología , Humanos , Inmunidad Humoral , Glicoproteína de la Espiga del Coronavirus , Linfocitos T
3.
Cell ; 185(5): 872-880.e3, 2022 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-35123650

RESUMEN

Although infections among vaccinated individuals lead to milder COVID-19 symptoms relative to those in unvaccinated subjects, the specificity and durability of antibody responses elicited by breakthrough cases remain unknown. Here, we demonstrate that breakthrough infections induce serum-binding and -neutralizing antibody responses that are markedly more potent, durable, and resilient to spike mutations observed in variants than those in subjects who received only 2 doses of vaccine. However, we show that breakthrough cases, subjects who were vaccinated after infection, and individuals vaccinated three times have serum-neutralizing activity of comparable magnitude and breadth, indicating that an increased number of exposures to SARS-CoV-2 antigen(s) enhance the quality of antibody responses. Neutralization of SARS-CoV was moderate, however, underscoring the importance of developing vaccines eliciting broad sarbecovirus immunity for pandemic preparedness.

4.
Cell ; 184(11): 2927-2938.e11, 2021 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-34010620

RESUMEN

Defining long-term protective immunity to SARS-CoV-2 is one of the most pressing questions of our time and will require a detailed understanding of potential ways this virus can evolve to escape immune protection. Immune protection will most likely be mediated by antibodies that bind to the viral entry protein, spike (S). Here, we used Phage-DMS, an approach that comprehensively interrogates the effect of all possible mutations on binding to a protein of interest, to define the profile of antibody escape to the SARS-CoV-2 S protein using coronavirus disease 2019 (COVID-19) convalescent plasma. Antibody binding was common in two regions, the fusion peptide and the linker region upstream of the heptad repeat region 2. However, escape mutations were variable within these immunodominant regions. There was also individual variation in less commonly targeted epitopes. This study provides a granular view of potential antibody escape pathways and suggests there will be individual variation in antibody-mediated virus evolution.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , Epítopos/inmunología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Algoritmos , COVID-19/terapia , COVID-19/virología , Línea Celular , Biblioteca de Genes , Humanos , Inmunización Pasiva , Mutación , Dominios Proteicos , SARS-CoV-2/genética , Programas Informáticos , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Sueroterapia para COVID-19
5.
Cell ; 183(5): 1367-1382.e17, 2020 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-33160446

RESUMEN

A safe, effective, and scalable vaccine is needed to halt the ongoing SARS-CoV-2 pandemic. We describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 SARS-CoV-2 spike receptor-binding domains (RBDs) in a highly immunogenic array and induce neutralizing antibody titers 10-fold higher than the prefusion-stabilized spike despite a 5-fold lower dose. Antibodies elicited by the RBD nanoparticles target multiple distinct epitopes, suggesting they may not be easily susceptible to escape mutations, and exhibit a lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. The high yield and stability of the assembled nanoparticles suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms and have launched cGMP manufacturing efforts to advance the SARS-CoV-2-RBD nanoparticle vaccine into the clinic.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Nanopartículas/química , Dominios Proteicos/inmunología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Vacunación , Adolescente , Adulto , Anciano , Animales , COVID-19/virología , Chlorocebus aethiops , Estudios de Cohortes , Epítopos/inmunología , Femenino , Células HEK293 , Humanos , Macaca nemestrina , Masculino , Ratones Endogámicos BALB C , Persona de Mediana Edad , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Células Vero , Adulto Joven
6.
Nature ; 631(8021): 617-626, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38961298

RESUMEN

SARS-CoV-2 variants acquire mutations in the spike protein that promote immune evasion1 and affect other properties that contribute to viral fitness, such as ACE2 receptor binding and cell entry2,3. Knowledge of how mutations affect these spike phenotypes can provide insight into the current and potential future evolution of the virus. Here we use pseudovirus deep mutational scanning4 to measure how more than 9,000 mutations across the full XBB.1.5 and BA.2 spikes affect ACE2 binding, cell entry or escape from human sera. We find that mutations outside the receptor-binding domain (RBD) have meaningfully affected ACE2 binding during SARS-CoV-2 evolution. We also measure how mutations to the XBB.1.5 spike affect neutralization by serum from individuals who recently had SARS-CoV-2 infections. The strongest serum escape mutations are in the RBD at sites 357, 420, 440, 456 and 473; however, the antigenic effects of these mutations vary across individuals. We also identify strong escape mutations outside the RBD; however, many of them decrease ACE2 binding, suggesting they act by modulating RBD conformation. Notably, the growth rates of human SARS-CoV-2 clades can be explained in substantial part by the measured effects of mutations on spike phenotypes, suggesting our data could enable better prediction of viral evolution.


Asunto(s)
Análisis Mutacional de ADN , Evolución Molecular , Aptitud Genética , Evasión Inmune , Mutación , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Humanos , Enzima Convertidora de Angiotensina 2/metabolismo , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Sitios de Unión , COVID-19/inmunología , COVID-19/virología , Aptitud Genética/genética , Evasión Inmune/genética , Pruebas de Neutralización , Unión Proteica , Dominios Proteicos/genética , SARS-CoV-2/genética , SARS-CoV-2/inmunología , SARS-CoV-2/clasificación , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/inmunología , Internalización del Virus , Células HEK293
7.
Immunity ; 53(1): 98-105.e5, 2020 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-32561270

RESUMEN

Antibody responses develop following SARS-CoV-2 infection, but little is known about their epitope specificities, clonality, binding affinities, epitopes, and neutralizing activity. We isolated B cells specific for the SARS-CoV-2 envelope glycoprotein spike (S) from a COVID-19-infected subject 21 days after the onset of clinical disease. 45 S-specific monoclonal antibodies were generated. They had undergone minimal somatic mutation with limited clonal expansion, and three bound the receptor-binding domain (RBD). Two antibodies neutralized SARS-CoV-2. The most potent antibody bound the RBD and prevented binding to the ACE2 receptor, while the other bound outside the RBD. Thus, most anti-S antibodies that were generated in this patient during the first weeks of COVID-19 infection were non-neutralizing and target epitopes outside the RBD. Antibodies that disrupt the SARS-CoV-2 S-ACE2 interaction can potently neutralize the virus without undergoing extensive maturation. Such antibodies have potential preventive and/or therapeutic potential and can serve as templates for vaccine design.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Betacoronavirus/inmunología , Hipermutación Somática de Inmunoglobulina/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Enzima Convertidora de Angiotensina 2 , Anticuerpos Monoclonales/inmunología , Linfocitos B/inmunología , Sitios de Unión , COVID-19 , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Epítopos de Linfocito B/inmunología , Humanos , Pandemias/prevención & control , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/inmunología , Neumonía Viral/prevención & control , Unión Proteica , Receptores Virales/metabolismo , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/metabolismo , Vacunas Virales/inmunología
8.
PLoS Pathog ; 20(8): e1012383, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39093891

RESUMEN

The SARS-CoV-2 virus responsible for the COVID-19 global pandemic has exhibited a striking capacity for viral evolution that drives continued evasion from vaccine and infection-induced immune responses. Mutations in the receptor binding domain of the S1 subunit of the spike glycoprotein have led to considerable escape from antibody responses, reducing the efficacy of vaccines and monoclonal antibody (mAb) therapies. Therefore, there is a need to interrogate more constrained regions of spike, such as the S2 subdomain. Here, we present a collection of S2 mAbs from two SARS-CoV-2 convalescent individuals that target multiple regions in S2, including regions outside of those commonly reported. One of the S2 mAbs, C20.119, which bound to a highly conserved epitope in the fusion peptide, was able to broadly neutralize across SARS-CoV-2 variants, SARS-CoV-1, and closely related zoonotic sarbecoviruses. The majority of the mAbs were non-neutralizing; however, many of them could mediate antibody-dependent cellular cytotoxicity (ADCC) at levels similar to the S1-targeting mAb S309 that was previously authorized for treatment of SARS-CoV-2 infections. Several of the mAbs with ADCC function also bound to spike trimers from other human coronaviruses (HCoVs), such as MERS-CoV and HCoV-HKU1. Our findings suggest S2 mAbs can target diverse epitopes in S2, including functional mAbs with HCoV and sarbecovirus breadth that likely target functionally constrained regions of spike. These mAbs could be developed for potential future pandemics, while also providing insight into ideal epitopes for eliciting a broad HCoV response.


Asunto(s)
Anticuerpos Monoclonales , Anticuerpos Antivirales , COVID-19 , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Glicoproteína de la Espiga del Coronavirus/inmunología , Humanos , SARS-CoV-2/inmunología , COVID-19/inmunología , COVID-19/virología , Anticuerpos Antivirales/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Epítopos/inmunología , Pandemias , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Neumonía Viral/inmunología , Neumonía Viral/virología , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología
9.
Proc Natl Acad Sci U S A ; 120(23): e2220948120, 2023 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-37253011

RESUMEN

The antiviral benefit of antibodies can be compromised by viral escape especially for rapidly evolving viruses. Therefore, durable, effective antibodies must be both broad and potent to counter newly emerging, diverse strains. Discovery of such antibodies is critically important for SARS-CoV-2 as the global emergence of new variants of concern (VOC) has compromised the efficacy of therapeutic antibodies and vaccines. We describe a collection of broad and potent neutralizing monoclonal antibodies (mAbs) isolated from an individual who experienced a breakthrough infection with the Delta VOC. Four mAbs potently neutralize the Wuhan-Hu-1 vaccine strain, the Delta VOC, and also retain potency against the Omicron VOCs through BA.4/BA.5 in both pseudovirus-based and authentic virus assays. Three mAbs also retain potency to recently circulating VOCs XBB.1.5 and BQ.1.1 and one also potently neutralizes SARS-CoV-1. The potency of these mAbs was greater against Omicron VOCs than all but one of the mAbs that had been approved for therapeutic applications. The mAbs target distinct epitopes on the spike glycoprotein, three in the receptor-binding domain (RBD) and one in an invariant region downstream of the RBD in subdomain 1 (SD1). The escape pathways we defined at single amino acid resolution with deep mutational scanning show they target conserved, functionally constrained regions of the glycoprotein, suggesting escape could incur a fitness cost. Overall, these mAbs are unique in their breadth across VOCs, their epitope specificity, and include a highly potent mAb targeting a rare epitope outside of the RBD in SD1.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Infección Irruptiva , Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Epítopos , Glicoproteína de la Espiga del Coronavirus/genética , Anticuerpos Antivirales
10.
Immunol Rev ; 309(1): 8-11, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35770708

RESUMEN

Pandemics have devastating effects that can be mitigated with the existence of global infrastructure for pandemic preparedness along with the adaptation of existing research studies and establishment of biorepositories early in an outbreak. Observational cohort studies in place prior to a pandemic, that are rapidly scalable in response to emerging infectious diseases, are essential for both the early pandemic response and evaluation of its long-term effects. The ability to quickly collect and share samples from convalescent individuals is also critical for the development of vaccines and therapeutics. We provide a reflection on key lessons learned from establishing a longitudinal observational cohort study during the SARS-CoV-2 pandemic in order to provide guidance for future pandemic preparedness.


Asunto(s)
COVID-19 , Pandemias , Estudios de Cohortes , Brotes de Enfermedades , Humanos , Estudios Observacionales como Asunto , Pandemias/prevención & control , SARS-CoV-2
11.
Lancet ; 403(10433): 1241-1253, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38367641

RESUMEN

BACKGROUND: Infants and young children born prematurely are at high risk of severe acute lower respiratory infection (ALRI) caused by respiratory syncytial virus (RSV). In this study, we aimed to assess the global disease burden of and risk factors for RSV-associated ALRI in infants and young children born before 37 weeks of gestation. METHODS: We conducted a systematic review and meta-analysis of aggregated data from studies published between Jan 1, 1995, and Dec 31, 2021, identified from MEDLINE, Embase, and Global Health, and individual participant data shared by the Respiratory Virus Global Epidemiology Network on respiratory infectious diseases. We estimated RSV-associated ALRI incidence in community, hospital admission, in-hospital mortality, and overall mortality among children younger than 2 years born prematurely. We conducted two-stage random-effects meta-regression analyses accounting for chronological age groups, gestational age bands (early preterm, <32 weeks gestational age [wGA], and late preterm, 32 to <37 wGA), and changes over 5-year intervals from 2000 to 2019. Using individual participant data, we assessed perinatal, sociodemographic, and household factors, and underlying medical conditions for RSV-associated ALRI incidence, hospital admission, and three severity outcome groups (longer hospital stay [>4 days], use of supplemental oxygen and mechanical ventilation, or intensive care unit admission) by estimating pooled odds ratios (ORs) through a two-stage meta-analysis (multivariate logistic regression and random-effects meta-analysis). This study is registered with PROSPERO, CRD42021269742. FINDINGS: We included 47 studies from the literature and 17 studies with individual participant-level data contributed by the participating investigators. We estimated that, in 2019, 1 650 000 (95% uncertainty range [UR] 1 350 000-1 990 000) RSV-associated ALRI episodes, 533 000 (385 000-730 000) RSV-associated hospital admissions, 3050 (1080-8620) RSV-associated in-hospital deaths, and 26 760 (11 190-46 240) RSV-attributable deaths occurred in preterm infants worldwide. Among early preterm infants, the RSV-associated ALRI incidence rate and hospitalisation rate were significantly higher (rate ratio [RR] ranging from 1·69 to 3·87 across different age groups and outcomes) than for all infants born at any gestational age. In the second year of life, early preterm infants and young children had a similar incidence rate but still a significantly higher hospitalisation rate (RR 2·26 [95% UR 1·27-3·98]) compared with all infants and young children. Although late preterm infants had RSV-associated ALRI incidence rates similar to that of all infants younger than 1 year, they had higher RSV-associated ALRI hospitalisation rate in the first 6 months (RR 1·93 [1·11-3·26]). Overall, preterm infants accounted for 25% (95% UR 16-37) of RSV-associated ALRI hospitalisations in all infants of any gestational age. RSV-associated ALRI in-hospital case fatality ratio in preterm infants was similar to all infants. The factors identified to be associated with RSV-associated ALRI incidence were mainly perinatal and sociodemographic characteristics, and factors associated with severe outcomes from infection were mainly underlying medical conditions including congenital heart disease, tracheostomy, bronchopulmonary dysplasia, chronic lung disease, or Down syndrome (with ORs ranging from 1·40 to 4·23). INTERPRETATION: Preterm infants face a disproportionately high burden of RSV-associated disease, accounting for 25% of RSV hospitalisation burden. Early preterm infants have a substantial RSV hospitalisation burden persisting into the second year of life. Preventive products for RSV can have a substantial public health impact by preventing RSV-associated ALRI and severe outcomes from infection in preterm infants. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe.


Asunto(s)
Recien Nacido Prematuro , Infecciones por Virus Sincitial Respiratorio , Infecciones del Sistema Respiratorio , Humanos , Infecciones por Virus Sincitial Respiratorio/epidemiología , Lactante , Factores de Riesgo , Recién Nacido , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/virología , Incidencia , Hospitalización/estadística & datos numéricos , Salud Global/estadística & datos numéricos , Preescolar , Virus Sincitial Respiratorio Humano , Mortalidad Hospitalaria , Femenino , Enfermedad Aguda
12.
J Immunol ; 210(9): 1236-1246, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-36961450

RESUMEN

mRNA vaccination of individuals with prior SARS-CoV-2 infection provides superior protection against breakthrough infections with variants of concern compared with vaccination in the absence of prior infection. However, the immune mechanisms by which this hybrid immunity is generated and maintained are unknown. Whereas genetic variation in spike glycoprotein effectively subverts neutralizing Abs, spike-specific T cells are generally maintained against SARS-CoV-2 variants. Thus, we comprehensively profiled human T cell responses against the S1 and S2 domains of spike glycoprotein in a cohort of SARS-CoV-2-naive (n = 13) or -convalescent (n = 17) individuals who received two-dose mRNA vaccine series and were matched by age, sex, and vaccine type. Using flow cytometry, we observed that the overall functional breadth of CD4 T cells and polyfunctional Th1 responses was similar between the two groups. However, polyfunctional cytotoxic CD4 T cell responses against both S1 and S2 domains trended higher among convalescent subjects. Multimodal single-cell RNA sequencing revealed diverse functional programs in spike-specific CD4 and CD8 T cells in both groups. However, convalescent individuals displayed enhanced cytotoxic and antiviral CD8 T cell responses to both S1 and S2 in the absence of cytokine production. Taken together, our data suggest that cytotoxic CD4 and CD8 T cells targeting spike glycoprotein may partially account for hybrid immunity and protection against breakthrough infections with SARS-CoV-2.


Asunto(s)
COVID-19 , Linfocitos T Citotóxicos , Humanos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/genética , Infección Irruptiva , ARN Mensajero , Vacunación , Inmunidad Adaptativa , Glicoproteínas , Anticuerpos Antivirales , Anticuerpos Neutralizantes
13.
Ann Intern Med ; 177(9): 1209-1221, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39133923

RESUMEN

BACKGROUND: There are currently no validated clinical biomarkers of postacute sequelae of SARS-CoV-2 infection (PASC). OBJECTIVE: To investigate clinical laboratory markers of SARS-CoV-2 and PASC. DESIGN: Propensity score-weighted linear regression models were fitted to evaluate differences in mean laboratory measures by prior infection and PASC index (≥12 vs. 0). (ClinicalTrials.gov: NCT05172024). SETTING: 83 enrolling sites. PARTICIPANTS: RECOVER-Adult cohort participants with or without SARS-CoV-2 infection with a study visit and laboratory measures 6 months after the index date (or at enrollment if >6 months after the index date). Participants were excluded if the 6-month visit occurred within 30 days of reinfection. MEASUREMENTS: Participants completed questionnaires and standard clinical laboratory tests. RESULTS: Among 10 094 participants, 8746 had prior SARS-CoV-2 infection, 1348 were uninfected, 1880 had a PASC index of 12 or higher, and 3351 had a PASC index of zero. After propensity score adjustment, participants with prior infection had a lower mean platelet count (265.9 × 109 cells/L [95% CI, 264.5 to 267.4 × 109 cells/L]) than participants without known prior infection (275.2 × 109 cells/L [CI, 268.5 to 282.0 × 109 cells/L]), as well as higher mean hemoglobin A1c (HbA1c) level (5.58% [CI, 5.56% to 5.60%] vs. 5.46% [CI, 5.40% to 5.51%]) and urinary albumin-creatinine ratio (81.9 mg/g [CI, 67.5 to 96.2 mg/g] vs. 43.0 mg/g [CI, 25.4 to 60.6 mg/g]), although differences were of modest clinical significance. The difference in HbA1c levels was attenuated after participants with preexisting diabetes were excluded. Among participants with prior infection, no meaningful differences in mean laboratory values were found between those with a PASC index of 12 or higher and those with a PASC index of zero. LIMITATION: Whether differences in laboratory markers represent consequences of or risk factors for SARS-CoV-2 infection could not be determined. CONCLUSION: Overall, no evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC. PRIMARY FUNDING SOURCE: National Institutes of Health.


Asunto(s)
Biomarcadores , COVID-19 , Síndrome Post Agudo de COVID-19 , SARS-CoV-2 , Humanos , COVID-19/complicaciones , COVID-19/diagnóstico , COVID-19/sangre , Masculino , Femenino , Persona de Mediana Edad , Biomarcadores/sangre , Puntaje de Propensión , Anciano , Adulto , Hemoglobina Glucada/análisis , Estudios de Cohortes
14.
J Infect Dis ; 229(Supplement_1): S51-S60, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-37824420

RESUMEN

BACKGROUND: With the licensure of maternal respiratory syncytial virus (RSV) vaccines in Europe and the United States, data are needed to better characterize the burden of RSV-associated acute respiratory infections (ARI) in pregnancy. The current study aimed to determine among pregnant individuals the proportion of ARI testing positive for RSV and the RSV incidence rate, RSV-associated hospitalizations, deaths, and perinatal outcomes. METHODS: We conducted a systematic review, following PRISMA 2020 guidelines, using 5 databases (Medline, Embase, Global Health, Web of Science, and Global Index Medicus), and including additional unpublished data. Pregnant individuals with ARI who had respiratory samples tested for RSV were included. We used a random-effects meta-analysis to generate overall proportions and rate estimates across studies. RESULTS: Eleven studies with pregnant individuals recruited between 2010 and 2022 were identified, most of which recruited pregnant individuals in community, inpatient and outpatient settings. Among 8126 pregnant individuals, the proportion with ARI that tested positive for RSV ranged from 0.9% to 10.7%, with a meta-estimate of 3.4% (95% confidence interval [CI], 1.9%-54%). The pooled incidence rate of RSV among pregnant individuals was 26.0 (95% CI, 15.8-36.2) per 1000 person-years. RSV hospitalization rates reported in 2 studies were 2.4 and 3.0 per 1000 person-years. In 5 studies that ascertained RSV-associated deaths among 4708 pregnant individuals, no deaths were reported. Three studies comparing RSV-positive and RSV-negative pregnant individuals found no difference in the odds of miscarriage, stillbirth, low birth weight, and small size for gestational age. RSV-positive pregnant individuals had higher odds of preterm delivery (odds ratio, 3.6 [95% CI, 1.3-10.3]). CONCLUSIONS: Data on RSV-associated hospitalization rates are limited, but available estimates are lower than those reported in older adults and young children. As countries debate whether to include RSV vaccines in maternal vaccination programs, which are primarily intended to protect infants, this information could be useful in shaping vaccine policy decisions.


Asunto(s)
Complicaciones Infecciosas del Embarazo , Infecciones por Virus Sincitial Respiratorio , Infecciones del Sistema Respiratorio , Femenino , Humanos , Embarazo , Bases de Datos Factuales , Europa (Continente) , Virus Sincitial Respiratorio Humano , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/virología , Infecciones por Virus Sincitial Respiratorio/epidemiología , Complicaciones Infecciosas del Embarazo/epidemiología , Complicaciones Infecciosas del Embarazo/virología
15.
J Infect Dis ; 229(2): 422-431, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-37531658

RESUMEN

BACKGROUND: The epidemiology of respiratory viral infections is complex. How infection with one respiratory virus affects risk of subsequent infection with the same or another respiratory virus is not well described. METHODS: From October 2019 to June 2021, enrolled households completed active surveillance for acute respiratory illness (ARI), and participants with ARI self-collected nasal swab specimens; after April 2020, participants with ARI or laboratory-confirmed severe acute respiratory syndrome coronavirus 2 and their household members self-collected nasal swab specimens. Specimens were tested using multiplex reverse-transcription polymerase chain reaction for respiratory viruses. A Cox regression model with a time-dependent covariate examined risk of subsequent detections following a specific primary viral detection. RESULTS: Rhinovirus was the most frequently detected pathogen in study specimens (406 [9.5%]). Among 51 participants with multiple viral detections, rhinovirus to seasonal coronavirus (8 [14.8%]) was the most common viral detection pairing. Relative to no primary detection, there was a 1.03-2.06-fold increase in risk of subsequent virus detection in the 90 days after primary detection; risk varied by primary virus: human parainfluenza virus, rhinovirus, and respiratory syncytial virus were statistically significant. CONCLUSIONS: Primary virus detection was associated with higher risk of subsequent virus detection within the first 90 days after primary detection.


Asunto(s)
Infecciones por Enterovirus , Virus Sincitial Respiratorio Humano , Infecciones del Sistema Respiratorio , Virosis , Virus , Humanos , Lactante , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/epidemiología , Washingtón/epidemiología , Virus/genética , Rhinovirus/genética
16.
J Infect Dis ; 230(2): 363-373, 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-38531685

RESUMEN

BACKGROUND: SARS-CoV-2 antigen-detection rapid diagnostic tests (Ag-RDTs) have become widely utilized but longitudinal characterization of their community-based performance remains incompletely understood. METHODS: This prospective longitudinal study at a large public university in Seattle, WA utilized remote enrollment, online surveys, and self-collected nasal swab specimens to evaluate Ag-RDT performance against real-time reverse transcription polymerase chain reaction (rRT-PCR) in the context of SARS-CoV-2 Omicron. Ag-RDT sensitivity and specificity within 1 day of rRT-PCR were evaluated by symptom status throughout the illness episode and Orf1b cycle threshold (Ct). RESULTS: From February to December 2022, 5757 participants reported 17 572 Ag-RDT results and completed 12 674 rRT-PCR tests, of which 995 (7.9%) were rRT-PCR positive. Overall sensitivity and specificity were 53.0% (95% confidence interval [CI], 49.6%-56.4%) and 98.8% (95% CI, 98.5%-99.0%), respectively. Sensitivity was comparatively higher for Ag-RDTs used 1 day after rRT-PCR (69.0%), 4-7 days after symptom onset (70.1%), and Orf1b Ct ≤20 (82.7%). Serial Ag-RDT sensitivity increased with repeat testing ≥2 (68.5%) and ≥4 (75.8%) days after an initial Ag-RDT-negative result. CONCLUSIONS: Ag-RDT performance varied by clinical characteristics and temporal testing patterns. Our findings support recommendations for serial testing following an initial Ag-RDT-negative result, especially among recently symptomatic persons or those at high risk for SARS-CoV-2 infection.


Asunto(s)
Prueba Serológica para COVID-19 , COVID-19 , SARS-CoV-2 , Sensibilidad y Especificidad , Humanos , COVID-19/diagnóstico , SARS-CoV-2/inmunología , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/genética , Estudios Prospectivos , Estudios Longitudinales , Masculino , Femenino , Persona de Mediana Edad , Adulto , Prueba Serológica para COVID-19/métodos , Antígenos Virales/análisis , Prueba de Ácido Nucleico para COVID-19/métodos , Anciano , Washingtón , Adulto Joven , Adolescente
17.
Emerg Infect Dis ; 30(11): 2250-2260, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39447143

RESUMEN

Congregate homeless shelters are disproportionately affected by infectious disease outbreaks. We describe enterovirus epidemiology across 23 adult and family shelters in King County, Washington, USA, during October 2019-May 2021, by using repeated cross-sectional respiratory illness and environmental surveillance and viral genome sequencing. Among 3,281 participants >3 months of age, we identified coxsackievirus A21 (CVA21) in 39 adult residents (3.0% [95% CI 1.9%-4.8%] detection) across 7 shelters during October 2019-February 2020. We identified enterovirus D68 (EV-D68) in 5 adult residents in 2 shelters during October-November 2019. Of 812 environmental samples, 1 was EV-D68-positive and 5 were CVA21-positive. Other enteroviruses detected among residents, but not in environmental samples, included coxsackievirus A6/A4 in 3 children. No enteroviruses were detected during April 2020-May 2021. Phylogenetically clustered CVA21 and EV-D68 cases occurred in some shelters. Some shelters also hosted multiple CVA21 lineages.


Asunto(s)
Enterovirus Humano D , Infecciones por Enterovirus , Personas con Mala Vivienda , Filogenia , Humanos , Washingtón/epidemiología , Personas con Mala Vivienda/estadística & datos numéricos , Masculino , Adulto , Femenino , Infecciones por Enterovirus/epidemiología , Infecciones por Enterovirus/virología , Enterovirus Humano D/genética , Enterovirus Humano D/clasificación , Persona de Mediana Edad , Genoma Viral , Preescolar , Niño , Enterovirus/genética , Enterovirus/clasificación , Adolescente , Lactante , Brotes de Enfermedades , Adulto Joven , Infecciones por Coxsackievirus/epidemiología , Infecciones por Coxsackievirus/virología , Estudios Transversales , Anciano , Vivienda
18.
J Clin Microbiol ; 62(2): e0128523, 2024 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-38131692

RESUMEN

The COVID-19 pandemic spurred the development of innovative solutions for specimen collection and molecular detection for large-scale community testing. Among these developments is the RHINOstic nasal swab, a plastic anterior nares swab built into the cap of a standard matrix tube that facilitates automated processing of up to 96 specimens at a time. In a study of unsupervised self-collection utilizing these swabs, we demonstrate comparable analytic performance and shipping stability compared to traditional anterior nares swabs, as well as significant improvements in laboratory processing efficiency. The use of these swabs may allow laboratories to accommodate large numbers of sample collections during periods of high testing demand. Automation-friendly nasal swabs are an important tool for high-throughput processing of samples that may be adopted in response to future respiratory viral pandemics.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/diagnóstico , Prueba de COVID-19 , Técnicas de Laboratorio Clínico , Pandemias , Manejo de Especímenes , Nasofaringe
19.
PLoS Pathog ; 18(6): e1010592, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35767821

RESUMEN

Exposure histories to SARS-CoV-2 variants and vaccinations will shape the specificity of antibody responses. To understand the specificity of Delta-elicited antibody immunity, we characterize the polyclonal antibody response elicited by primary or mRNA vaccine-breakthrough Delta infections. Both types of infection elicit a neutralizing antibody response focused heavily on the receptor-binding domain (RBD). We use deep mutational scanning to show that mutations to the RBD's class 1 and class 2 epitopes, including sites 417, 478, and 484-486 often reduce binding of these Delta-elicited antibodies. The anti-Delta antibody response is more similar to that elicited by early 2020 viruses than the Beta variant, with mutations to the class 1 and 2, but not class 3 epitopes, having the largest effects on polyclonal antibody binding. In addition, mutations to the class 1 epitope (e.g., K417N) tend to have larger effects on antibody binding and neutralization in the Delta spike than in the D614G spike, both for vaccine- and Delta-infection-elicited antibodies. These results help elucidate how the antigenic impacts of SARS-CoV-2 mutations depend on exposure history.


Asunto(s)
COVID-19 , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Formación de Anticuerpos , Epítopos , Humanos , Pruebas de Neutralización , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Vacunas Sintéticas , Vacunas de ARNm
20.
PLoS Pathog ; 18(4): e1010155, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35404959

RESUMEN

Macaques are a commonly used model for studying immunity to human viruses, including for studies of SARS-CoV-2 infection and vaccination. However, it is unknown whether macaque antibody responses resemble the response in humans. To answer this question, we employed a phage-based deep mutational scanning approach (Phage-DMS) to compare which linear epitopes are targeted on the SARS-CoV-2 Spike protein in convalescent humans, convalescent (re-infected) rhesus macaques, mRNA-vaccinated humans, and repRNA-vaccinated pigtail macaques. We also used Phage-DMS to determine antibody escape pathways within each epitope, enabling a granular comparison of antibody binding specificities at the locus level. Overall, we identified some common epitope targets in both macaques and humans, including in the fusion peptide (FP) and stem helix-heptad repeat 2 (SH-H) regions. Differences between groups included a response to epitopes in the N-terminal domain (NTD) and C-terminal domain (CTD) in vaccinated humans but not vaccinated macaques, as well as recognition of a CTD epitope and epitopes flanking the FP in convalescent macaques but not convalescent humans. There was also considerable variability in the escape pathways among individuals within each group. Sera from convalescent macaques showed the least variability in escape overall and converged on a common response with vaccinated humans in the SH-H epitope region, suggesting highly similar antibodies were elicited. Collectively, these findings suggest that the antibody response to SARS-CoV-2 in macaques shares many features with humans, but with substantial differences in the recognition of certain epitopes and considerable individual variability in antibody escape profiles, suggesting a diverse repertoire of antibodies that can respond to major epitopes in both humans and macaques. Differences in macaque species and exposure type may also contribute to these findings.


Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Formación de Anticuerpos , COVID-19/prevención & control , Vacunas contra la COVID-19 , Epítopos , Humanos , Macaca mulatta , Glicoproteína de la Espiga del Coronavirus , Vacunación
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