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Mutations in the spike glycoproteins of SARS-CoV-2 variants of concern have independently been shown to enhance aspects of spike protein fitness. Here, we describe an antibody fragment (V H ab6) that neutralizes all major variants including the recently emerged BA.1 and BA.2 Omicron subvariants, with a unique mode of binding revealed by cryo-EM studies. Further, we provide a comparative analysis of the mutational effects within previously emerged variant spikes and identify the structural role of mutations within the NTD and RBD in evading antibody neutralization. Our analysis shows that the highly mutated Gamma N-terminal domain exhibits considerable structural rearrangements, partially explaining its decreased neutralization by convalescent sera. Our results provide mechanistic insights into the structural, functional, and antigenic consequences of SARS-CoV-2 spike mutations and highlight a spike protein vulnerability that may be exploited to achieve broad protection against circulating variants. SARS-CoV-2 variants have accumulated multiple defining mutations within their spike glycoproteins. Here, the authors report a structural basis for broad neutralization of several variants by a heavy chain antibody fragment and provide a mutational analysis focusing on antibody evasion, receptor engagement, and spike protein structure.

Background Dengue remains a major public health threat worldwide, particularly in the pediatric population. Dengue illness can develop from infection with any of the four dengue virus serotypes (DENV1-4), ranging from mild fever to potentially life-threatening severe dengue. In children, most dengue infections present as an undifferentiated fever, making it difficult to distinguish dengue from several other common viral infections that frequently occur at early ages. Thus, the rapid identification of dengue cases followed by appropriate early interventions and management is crucial to improve clinical prognosis. In this study, we evaluated socio-demographic, clinical, and laboratory factors predictive of disease severity in children and adolescents in Northeast Brazil. Methods Patients aged < 1–19 years old ( n  = 288) hospitalized with dengue in a reference hospital between 2017 and 2020 were included in the study. Dengue patients were classified as dengue with warning signs (DwWS) and severe dengue (SD). Individual and sociodemographic information was retrieved from the hospital’s epidemiological investigation forms. Clinical data and laboratory parameters collected at the time of admission to the hospital were extracted from the medical records. Results Out of 288 patients, 72.2% (208/288) were classified as DwWS. We observed a steady decline in the number of hospitalizations by SD in the pediatric population during the study period, including in the epidemic year of 2019. SD cases were more frequently observed in children aged 7–12 years old (OR = 3.72, 95%CI = 1.34–13.21) and with self-identified mixed (OR = 2.28, 95%CI = 1.22–4.52) and black (OR = 5.92, 95%CI = 1.73–21.1) race. Multivariate analysis showed irritability (OR = 3.69, 95%CI = 1.36–11.19), fluid accumulation (OR = 5.50, 95%CI = 1.51–23.63), and lethargy/restlessness (OR = 19.95, 95%CI = 6.47–73.23) as significant parameters predictive of SD at hospitalization. Binary logistic regression indicated that increased levels of aspartate aminotransferase (AST; p-value = 0.003), monocytes (p-value < 0.0001), basophils (p-value = 0.0003), and red cell distribution width (RDW) percentage (p-value = 0.005) at admission are among the laboratory parameters associated with SD in the study population. Conclusions The socio-demographic (age and race), clinical signs and symptoms (irritability, fluid accumulation, and lethargy/restlessness), and laboratory parameters (AST, monocytes, basophils, and RDW) identified in our study can help clinicians in the prompt diagnosis of the disease and in identifying patients who require immediate intervention and intensive care.

The microcephaly epidemic, which started in Brazil in 2015, was declared a Public Health Emergency of International Concern by WHO in 2016. We report the preliminary results of a case-control study investigating the association between microcephaly and Zika virus infection during pregnancy. We did this case-control study in eight public hospitals in Recife, Brazil. Cases were neonates with microcephaly. Two controls (neonates without microcephaly), matched by expected date of delivery and area of residence, were selected for each case. Serum samples of cases and controls and cerebrospinal fluid samples of cases were tested for Zika virus-specific IgM and by quantitative RT-PCR. Laboratory-confirmed Zika virus infection during pregnancy was defined as detection of Zika virus-specific IgM or a positive RT-PCR result in neonates. Maternal serum samples were tested by plaque reduction neutralisation assay for Zika virus and dengue virus. We estimated crude odds ratios (ORs) and 95% CIs using a median unbiased estimator for binary data in an unconditional logistic regression model. We estimated ORs separately for cases with and without radiological evidence of brain abnormalities. Between Jan 15, 2016, and May 2, 2016, we prospectively recruited 32 cases and 62 controls. 24 (80%) of 30 mothers of cases had Zika virus infection compared with 39 (64%) of 61 mothers of controls (p=0·12). 13 (41%) of 32 cases and none of 62 controls had laboratory-confirmed Zika virus infection; crude overall OR 55·5 (95% CI 8·6–∞); OR 113·3 (95% CI 14·5–∞) for seven cases with brain abnormalities; and OR 24·7 (95% CI 2·9–∞) for four cases without brain abnormalities. Our data suggest that the microcephaly epidemic is a result of congenital Zika virus infection. We await further data from this ongoing study to assess other potential risk factors and to confirm the strength of association in a larger sample size. Brazilian Ministry of Health, Pan American Health Organization, and Enhancing Research Activity in Epidemic Situations.

The emergence of SARS-CoV-2 variants of concern (VOCs) requires the development of next-generation biologics that are effective against a variety of strains of the virus. Herein, we characterize a human V domain, F6, which we generated by sequentially panning large phage displayed V libraries against receptor binding domains (RBDs) containing VOC mutations. Cryo-EM analyses reveal that F6 has a unique binding mode that spans a broad surface of the RBD and involves the antibody framework region. Attachment of an Fc region to a fusion of F6 and ab8, a previously characterized V domain, resulted in a construct (F6-ab8-Fc) that neutralized Omicron pseudoviruses with a half-maximal neutralizing concentration (IC ) of 4.8 nM . Additionally, prophylactic treatment using F6-ab8-Fc reduced live Beta (B.1.351) variant viral titers in the lungs of a mouse model. Our results provide a new potential therapeutic against SARS-CoV-2 VOCs - including the recently emerged Omicron variant - and highlight a vulnerable epitope within the spike protein RBD that may be exploited to achieve broad protection against circulating variants.

Mutations in the spike glycoproteins of SARS-CoV-2 variants of concern have independently been shown to enhance aspects of spike protein fitness. Here, we report the discovery of a novel antibody fragment (VH ab6) that neutralizes all major variants, with a unique mode of binding revealed by cryo-EM studies. Further, we provide a comparative analysis of the mutational effects within variant spikes and identify the structural role of mutations within the NTD and RBD in evading antibody neutralization. Our analysis shows that the highly mutated Gamma N-terminal domain exhibits considerable structural rearrangements, partially explaining its decreased neutralization by convalescent sera. Our results provide mechanistic insights into the structural, functional, and antigenic consequences of SARS-CoV-2 spike mutations and highlight a spike protein vulnerability that may be exploited to achieve broad protection against circulating variants. Competing Interest Statement Wei Li and Dimiter S. Dimitrov are coinventors of a patent, filed by the University of Pittsburgh, related to ab1 and ab8 described in this manuscript. Sriram Subramaniam is Founder and CEO of Gandeeva Therapeutics Inc.