Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged coronavirus that is responsible for the current pandemic of coronavirus disease 2019 (COVID-19), which has resulted in ...more than 3.7 million infections and 260,000 deaths as of 6 May 2020
. Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies. Here we describe several monoclonal antibodies that target the S glycoprotein of SARS-CoV-2, which we identified from memory B cells of an individual who was infected with severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003. One antibody (named S309) potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2, by engaging the receptor-binding domain of the S glycoprotein. Using cryo-electron microscopy and binding assays, we show that S309 recognizes an epitope containing a glycan that is conserved within the Sarbecovirus subgenus, without competing with receptor attachment. Antibody cocktails that include S309 in combination with other antibodies that we identified further enhanced SARS-CoV-2 neutralization, and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309 and antibody cocktails containing S309 for prophylaxis in individuals at a high risk of exposure or as a post-exposure therapy to limit or treat severe disease.
Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. ...In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.
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•SARS-CoV-2 RBD is immunodominant and accounts for 90% of serum neutralizing activity•RBD antibodies decline with a half-life of ∼50 days, but their avidity increases•Structural definition of a SARS-CoV-2 RBD antigenic map using monoclonal antibodies•ACE2-binding site dominates SARS-CoV-2 polyclonal neutralizing antibody responses
Serological analyses of ∼650 SARS-CoV-2-exposed individuals show that 90% of the serum or plasma neutralizing activity targets the virus receptor-binding domain, with structural insights revealing how distinct types of neutralizing antibodies targeting the ACE2-binding site dominate the immune response against SARS-CoV-2 spike.
Three highly pathogenic β-coronaviruses have crossed the animal-to-human species barrier in the past two decades: SARS-CoV, MERS-CoV and SARS-CoV-2. To evaluate the possibility of identifying ...antibodies with broad neutralizing activity, we isolated a monoclonal antibody, termed B6, that cross-reacts with eight β-coronavirus spike glycoproteins, including all five human-infecting β-coronaviruses. B6 broadly neutralizes entry of pseudotyped viruses from lineages A and C, but not from lineage B, and the latter includes SARS-CoV and SARS-CoV-2. Cryo-EM, X-ray crystallography and membrane fusion assays reveal that B6 binds to a conserved cryptic epitope located in the fusion machinery. The data indicate that antibody binding sterically interferes with the spike conformational changes leading to membrane fusion. Our data provide a structural framework explaining B6 cross-reactivity with β-coronaviruses from three lineages, along with a proof of concept for antibody-mediated broad coronavirus neutralization elicited through vaccination. This study unveils an unexpected target for next-generation structure-guided design of a pan-β-coronavirus vaccine.
An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape
, have activity against diverse sarbecoviruses
, and be highly protective through viral neutralization
and effector functions
. ...Understanding how these properties relate to each other and vary across epitopes would aid the development of therapeutic antibodies and guide vaccine design. Here we comprehensively characterize escape, breadth and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E12
) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.
Background: Infants, toddlers and preschoolers are the highest risk group for burn injury. However, to date this population has been largely neglected. This study examined the prevalence, onset, ...comorbidity and recovery patterns of posttrauma reactions in young children with burns.
Methods: Parents of 130 unintentionally burned children (1–6 years) participated in the study. The Diagnostic Infant Preschool Assessment was conducted with parents at 1 and 6 months postinjury.
Results: The majority of children were resilient. However, 35% were diagnosed with at least one psychological disorder, there was a high rate of comorbidity with posttraumatic stress disorder, and 8% of children did not experience recovery in distress levels over the course of 6 months.
Conclusions: These outcomes are likely to have serious repercussions for a young child’s medical and psychosocial recovery as well as their normal developmental trajectories. It is recommended that screening, prevention and early intervention resources are incorporated into paediatric health care settings to optimise children’s psychological adjustment following burn injury.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We ...show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant-neutralizing antibody that is a strong candidate for clinical development.
Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against SARS-CoV-2 variants and future zoonotic sarbecoviruses. We describe the isolation and ...characterization of a human monoclonal antibody, designated S2K146, that broadly neutralizes viruses belonging to SARS-CoV- and SARS-CoV-2-related sarbecovirus clades which use ACE2 as an entry receptor. Structural and functional studies show that most of the virus residues that directly bind S2K146 are also involved in binding to ACE2. This allows the antibody to potently inhibit receptor attachment. S2K146 protects against SARS-CoV-2 Beta challenge in hamsters and viral passaging experiments reveal a high barrier for emergence of escape mutants, making it a good candidate for clinical development. The conserved ACE2-binding residues present a site of vulnerability that might be leveraged for developing vaccines eliciting broad sarbecovirus immunity.
Undocumented Latino Immigrants and the Latino Health Paradox Lopez Mercado, Damaris; Rivera-González, Alexandra C.; Stimpson, Jim P. ...
American journal of preventive medicine,
August 2023, 2023-08-00, 20230801, Letnik:
65, Številka:
2
Journal Article
Recenzirano
Despite having worse healthcare access and other social disadvantages, immigrants have, on average, better health outcomes than U.S.-born individuals. For Latino immigrants, this is known as the ...Latino health paradox. It is unknown whether this phenomenon applies to undocumented immigrants.
This study used restricted California Health Interview Survey data from 2015 to 2020. Data were analyzed to test the relationships between citizenship/documentation status and physical and mental health among Latinos and U.S.-born Whites. Analyses were stratified by sex (male/female) and length of U.S. residence (<15 years/>= 15 years).
Undocumented Latino immigrants had lower predicted probabilities of reporting any health condition, asthma, and serious psychological distress and had a higher probability of overweight/obesity than U.S.-born Whites. Despite having a higher probability of overweight/obesity, undocumented Latino immigrants did not have probabilities of reporting diabetes, high blood pressure, or heart disease different from those of U.S.-born Whites after adjusting for having a usual source of care. Undocumented Latina women had a lower predicted probability of reporting any health condition and a higher predicted probability of overweight/obesity than U.S.-born White women. Undocumented Latino men had a lower predicted probability of reporting serious psychological distress than U.S.-born White men. There were no differences in outcomes when comparing shorter- with longer-duration undocumented Latino immigrants.
This study observed that the Latino health paradox may express patterns for undocumented Latino immigrants that are different from those for other Latino immigrant groups, emphasizing the importance of accounting for documentation status when conducting research on this population.
Trauma in Early Childhood: A Neglected Population De Young, Alexandra C.; Kenardy, Justin A.; Cobham, Vanessa E.
Clinical child and family psychology review,
09/2011, Letnik:
14, Številka:
3
Journal Article
Recenzirano
Infants, toddlers and preschoolers are a high risk group for exposure to trauma. Young children are also vulnerable to experiencing adverse outcomes as they are undergoing a rapid developmental ...period, have limited coping skills and are strongly dependent on their primary caregiver to protect them physically and emotionally. However, although millions of young children experience trauma each year, this population has been largely neglected. Fortunately, over the last 2 decades there has been a growing appreciation of the magnitude of the problem with a small but expanding number of dedicated researchers and clinicians working with this population. This review examines the empirical literature on trauma in young children with regards to the following factors: (1) how trauma reactions typically manifest in young children; (2) history and diagnostic validity of posttraumatic stress disorder (PTSD) in preschoolers; (3) prevalence, comorbidity and course of trauma reactions; (4) developmental considerations; (5) risk and protective factors; and (6) treatment. The review highlights that there are unique developmental differences in the rate and manifestation of trauma symptomatology, the current
Diagnostic and Statistical Manual of Mental Disorders
(4th ed., DSM-IV-TR) PTSD criteria is not developmentally sensitive and the impact of trauma must be considered within the context of the parent–child relationship. Recommendations for future research with this population are also discussed.
Purpose of Review
This review summarizes the latest evidence and developments in the validation of PTSD diagnostic criteria for children 6 years and under (PTSD<6Y), discusses the limitations of the ...current diagnostic criteria, and highlights areas for future research.
Recent Findings
Research has found that the DSM-5 PTSD<6Y, and a similar version in the DC:0-5, currently provides the most developmentally sensitive classification of PTSD for young children. In contrast, preliminary evidence suggests that the ICD-11 criteria might not appropriately capture PTSD in young children.
Summary
The inclusion of PTSD<6Y, the first developmental subtype in the DSM-5, represents an important step towards having a diagnostic system that is developmentally sensitive and relevant across the life span. However, further validation work and research with regard to the definition of trauma and functional impairment as well as with the age-appropriate description of symptoms is needed, especially in the youngest age group (0–3 years).
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