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1.
Science ; 377(6606): eabq0839, 2022 08 05.
Article in English | MEDLINE | ID: mdl-35857620

ABSTRACT

To combat future severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles that present randomly arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against epitopes that are conserved and relatively occluded rather than variable, immunodominant, and exposed. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD nanoparticles in mice and macaques and observed stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains, including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants, including Omicrons, and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest that mosaic-8 RBD nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , Betacoronavirus , Coronavirus Infections , Epitopes , Nanoparticles , Spike Glycoprotein, Coronavirus , Zoonoses , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Disease Models, Animal , Epitopes/chemistry , Epitopes/immunology , Epitopes/therapeutic use , Macaca , Mice , Nanoparticles/therapeutic use , Protein Domains/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Zoonoses/prevention & control , Zoonoses/virology
3.
Farm. hosp ; 46(3): 1-5, May-Jun, 2022. tab
Article in Spanish | IBECS | ID: ibc-203872

ABSTRACT

Objetivo: Analizar las reacciones locales y sistémicas aparecidas trasla primera y segunda dosis de la vacuna BNT162b2 (Pfizer-BioNTech)frente a COVID-19 en una muestra de trabajadores de un hospital detercer nivel, e identificar los factores relacionados con una mayor reactogenicidada la vacuna.Método: Se empleó un cuestionario autoadministrado para entrevistar a291 trabajadores de un hospital de tercer nivel que recibieron la vacunaBNT162b2 frente a COVID-19 entre enero y marzo de 2021. El cuestionarioincluyó preguntas acerca de las variables sociodemográficas de losparticipantes, infección previa de COVID-19 y las reacciones locales ysistémicas tras la primera y segunda dosis de la vacuna.Resultados: La reacción más comúnmente informada fue el dolor enel lugar de la inyección, siendo más frecuente tras la primera dosis de lavacuna. Las reacciones sistémicas evaluadas se informaron con mayor frecuenciatras la segunda dosis de la vacuna. Las mujeres, los adultos másjóvenes y las personas con una infección previa por COVID-19 notificaronuna mayor reactogenicidad. Además, una alta reactogenicidad tras laprimera dosis estuvo relacionada con un mayor número de reaccionesadversas tras la segunda dosis de la vacuna.Conclusiones:La distribución de la reactogenicidad en el presenteestudio es consistente con los datos reportados en los estudios realizados con la vacuna BNT162b2, especialmente en términos de asociación conlas características de los participantes. Estos hallazgos pueden facilitarla identificación de personas con mayor probabilidad de presentar unaalta reactogenicidad a la vacuna, permitiéndonos anticipar su aparicióny tratamiento.


Objective: To analyze the local and systemic reactions that appearedafter the first and second dose of the BNT162b2 vaccine againstCOVID‑19 (Pfizer-BioNTech) in a sample of workers from a tertiary hospital,and to identify the factors related to greater vaccine reactogenicity.Method: A self-administered questionnaire was used to interview291 workers from a tertiary hospital who received the BNT162b2 vaccineagainst COVID-19 between January and March 2021. The questionnaireincluded questions about the sociodemographic variables of the participants,previous COVID-19 infection, and local and systemic reactions afterthe first and second dose of the vaccine.Results: The most common adverse reaction was soreness at the injectionsite, which was reported more frequently after the first dose of thevaccine. The systemic reactions evaluated were reported more frequentlyafter the second dose of the vaccine. Women, younger adults, and subjectswith a prior COVID-19 infection reported increased reactogenicity.Furthermore, high reactogenicity after the first dose was found to be relatedto a higher number of adverse reactions after the second dose of thevaccine.Conclusions: The distribution of reactogenicity in the present study isconsistent with the data reported in previous studies on the BNT162b2vaccine, especially in terms of its association with the participants’ characteristics. These findings could facilitate the identification of people ata higher risk of developing high reactogenicity to the vaccine, therebymaking it possible to anticipate the appearance of adverse reactions andplan for their treatment.


Subject(s)
Humans , Male , Female , Betacoronavirus/immunology , RNA, Messenger/immunology , Health Personnel , Drug-Related Side Effects and Adverse Reactions , Vaccines/adverse effects , Patient Safety , Pharmacy Service, Hospital , Case-Control Studies
4.
Gastroenterol. hepatol. (Ed. impr.) ; 45(5): 383-389, May. 2022.
Article in English | IBECS | ID: ibc-204308

ABSTRACT

The COVID-19 pandemic has been a challenge for countries and health professionals worldwide. Viral entry by ACE-2 receptor and an excessive activation of the immune system are key to understand both incidence and severity of disease. Inflammatory Bowel Disease (IBD) represents a special condition associated with an inordinate response of the immune system to external agents. IBD treatments have been associated to an increased risk of bacterial and viral infections. This has raised the question of possible higher incidence and severity of COVID-19 infection in IBD patients. Several papers have been published during this year of pandemic to answer that question. Moreover, COVID-19 vaccination offers great promise in controlling infection in patients with IBD. Based on current evidence, patients with IBD do not have a higher incidence of COVID-19 than the general population, and they do not have worse disease evolution. Advanced age and presence of a greater number of comorbidities have been associated with worse outcomes, similar to the general population. Corticosteroids are associated to an increased risk of COVID-19 infection, higher hospitalization rate and higher risk of severe COVID-19. 5-ASA/Sulfasalazine and Thiopurines have a possible increased risk of severe COVID-19, although studies are lacking. On the other hand, Anti-TNF may have a possible protective effect. It is recommended to maintain the treatment. Anti-IL-12/23, anti-integrins and tofacitinib have results comparable to anti-TNF. Based on the efficacy, expert recommendations, and the absence of other evidence, it is recommended that patients with IBD be vaccinated.(AU)


La pandemia por COVID-19ha supuesto un reto para los países y sus profesionales sanitarios. La entrada viral en el hospedador a través del receptor ACE-2 y una activación excesiva del sistema inmunológico son claves para comprender tanto la incidencia como la gravedad de la enfermedad. La enfermedad inflamatoria intestinal (EII) representa una condición especial asociada con una respuesta descontrolada del sistema inmunológico a agentes externos. Los tratamientos para la EII se han asociado con un mayor riesgo de infecciones bacterianas y virales, lo que ha planteado la cuestión de una posible mayor incidencia y gravedad de la infección por COVID-19 en pacientes con EII. A lo largo del año 2021 se han publicado varios artículos que tratan de responder esta cuestión. La vacunación contra la COVID-19 ofrece una gran promesa para controlar la infección en pacientes con EII. Según la evidencia actual, los pacientes con EII no tienen mayor incidencia de COVID-19 ni peor evolución de la enfermedad en comparación con la población general. La edad avanzada y la presencia de un mayor número de comorbilidades se han asociado con peores resultados. Los corticosteroides están asociados con un mayor riesgo de infección por COVID-19, una mayor tasa de hospitalizaciones y un mayor riesgo de enfermedad grave. La mesalazina/sulfasalazina y las tiopurinas presentan un posible aumento del riesgo de COVID-19 grave, aunque se requieren más estudios para demostrar esta asociación. Dentro de los fármacos biológicos, los anti-TNF pueden tener un posible efecto protector. Los anti-IL-12/23, anti-integrinas y tofacitinib presentan resultados comparables con anti-TNF. Se recomienda mantener el tratamiento con agentes biológicos. Con base en la eficacia, las recomendaciones de los expertos y la ausencia de otra evidencia, se recomienda la vacunación de pacientes con EII.(AU)


Subject(s)
Humans , Male , Female , Vaccines , Betacoronavirus/immunology , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/drug therapy , Pandemics , Gastroenterology , Communicable Diseases
7.
Science ; 375(6579): 449-454, 2022 Jan 28.
Article in English | MEDLINE | ID: mdl-34990214

ABSTRACT

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.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Viral/immunology , Betacoronavirus/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/therapy , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/chemistry , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/chemistry , Antibodies, Viral/metabolism , Antibody Affinity , Broadly Neutralizing Antibodies/chemistry , Broadly Neutralizing Antibodies/metabolism , Broadly Neutralizing Antibodies/therapeutic use , COVID-19/immunology , Cross Reactions , Cryoelectron Microscopy , Epitopes , Humans , Immune Evasion , Mesocricetus , Models, Molecular , Molecular Mimicry , Mutation , Protein Conformation , Protein Domains , Receptors, Coronavirus/chemistry , Receptors, Coronavirus/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
8.
Science ; 375(6578): eabl6251, 2022 01 21.
Article in English | MEDLINE | ID: mdl-34855508

ABSTRACT

Many studies have examined the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants on neutralizing antibody activity after they have become dominant strains. Here, we evaluate the consequences of further viral evolution. We demonstrate mechanisms through which the SARS-CoV-2 receptor binding domain (RBD) can tolerate large numbers of simultaneous antibody escape mutations and show that pseudotypes containing up to seven mutations, as opposed to the one to three found in previously studied variants of concern, are more resistant to neutralization by therapeutic antibodies and serum from vaccine recipients. We identify an antibody that binds the RBD core to neutralize pseudotypes for all tested variants but show that the RBD can acquire an N-linked glycan to escape neutralization. Our findings portend continued emergence of escape variants as SARS-CoV-2 adapts to humans.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Immune Evasion , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , BNT162 Vaccine/immunology , Betacoronavirus/immunology , COVID-19/immunology , COVID-19/virology , Cross Reactions , Cryoelectron Microscopy , Crystallography, X-Ray , Epitopes , Evolution, Molecular , Humans , Models, Molecular , Mutation , Polysaccharides/analysis , Protein Binding , Protein Domains , Receptors, Coronavirus/chemistry , Receptors, Coronavirus/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Pseudotyping
9.
J Med Virol ; 94(1): 186-196, 2022 01.
Article in English | MEDLINE | ID: mdl-34427932

ABSTRACT

In classical viral infections, the avidity of immunoglobulin G (IgG) is low during acute infection and high a few months later. As recently reported, SARS-CoV-2 infections are not following this scheme, but they are rather characterized by incomplete avidity maturation. This study was performed to clarify whether infection with seasonal coronaviruses also leads to incomplete avidity maturation. The avidity of IgG toward the nucleoprotein (NP) of the seasonal coronaviruses 229E, NL63, OC43, HKU1 and of SARS-CoV-2 was determined in the sera from 88 healthy, SARS-CoV-2-negative subjects and in the sera from 70 COVID-19 outpatients, using the recomLine SARS-CoV-2 assay with recombinant antigens. In the sera from SARS-CoV-2-negative subjects, incomplete avidity maturation (persistent low and intermediate avidity indices) was the lowest for infections with the alpha-coronaviruses 229E (33.3%) and NL63 (61.3%), and the highest for the beta-coronaviruses OC43 (77.5%) and HKU1 (71.4%). In the sera from COVID-19 patients, the degree of incomplete avidity maturation of IgG toward NP of 223E, OC43, and HKU1 was not significantly different from that found in SARS-CoV-2-negative subjects, but a significant increase in avidity was observed for IgG toward NP of NL63. Though there was no cross-reaction between SARS-CoV-2 and seasonal coronaviruses, higher concentrations of IgG directed toward seasonal coronaviruses seemed to indirectly increase avidity maturation of IgG directed toward SARS-CoV-2. Our data show that incomplete IgG avidity maturation represents a characteristic consequence of coronavirus infections. This raises problems for the serological differentiation between acute and past infections and may be important for the biology of coronaviruses.


Subject(s)
Alphacoronavirus/immunology , Antibody Affinity , Betacoronavirus/immunology , COVID-19/immunology , Coronavirus Infections/immunology , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Antibodies, Viral/blood , Antibodies, Viral/immunology , Coronavirus NL63, Human/immunology , Coronavirus Nucleocapsid Proteins/immunology , Coronavirus OC43, Human/immunology , Cross Reactions , Female , Humans , Immunoglobulin G/blood , Male , Middle Aged , Phosphoproteins/immunology , Seasons , Young Adult
11.
Viruses ; 13(11)2021 11 21.
Article in English | MEDLINE | ID: mdl-34835131

ABSTRACT

Many countries in sub-Saharan Africa have experienced lower COVID-19 caseloads and fewer deaths than countries in other regions worldwide. Under-reporting of cases and a younger population could partly account for these differences, but pre-existing immunity to coronaviruses is another potential factor. Blood samples from Sierra Leonean Lassa fever and Ebola survivors and their contacts collected before the first reported COVID-19 cases were assessed using enzyme-linked immunosorbent assays for the presence of antibodies binding to proteins of coronaviruses that infect humans. Results were compared to COVID-19 subjects and healthy blood donors from the United States. Prior to the pandemic, Sierra Leoneans had more frequent exposures than Americans to coronaviruses with epitopes that cross-react with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), SARS-CoV, and Middle Eastern respiratory syndrome coronavirus (MERS-CoV). The percentage of Sierra Leoneans with antibodies reacting to seasonal coronaviruses was also higher than for American blood donors. Serological responses to coronaviruses by Sierra Leoneans did not differ by age or sex. Approximately a quarter of Sierra Leonian pre-pandemic blood samples had neutralizing antibodies against SARS-CoV-2 pseudovirus, while about a third neutralized MERS-CoV pseudovirus. Prior exposures to coronaviruses that induce cross-protective immunity may contribute to reduced COVID-19 cases and deaths in Sierra Leone.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Middle East Respiratory Syndrome Coronavirus/immunology , SARS-CoV-2/immunology , Age Distribution , Alphacoronavirus/immunology , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antigens, Viral/immunology , Betacoronavirus/immunology , Blood Donors , Coronavirus Nucleocapsid Proteins/immunology , Cross Protection , Cross Reactions , Epitopes , Female , Humans , Male , Phosphoproteins/immunology , Sierra Leone , United States
12.
Viruses ; 13(10)2021 09 22.
Article in English | MEDLINE | ID: mdl-34696329

ABSTRACT

Antibodies targeting the spike (S) and nucleocapsid (N) proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are essential tools. In addition to important roles in the treatment and diagnosis of infection, the availability of high-quality specific antibodies for the S and N proteins is essential to facilitate basic research of virus replication and in the characterization of mutations responsible for variants of concern. We have developed panels of mouse and rabbit monoclonal antibodies (mAbs) to the SARS-CoV-2 spike receptor-binding domain (S-RBD) and N protein for functional and antigenic analyses. The mAbs to the S-RBD were tested for neutralization of native SARS-CoV-2, with several exhibiting neutralizing activity. The panels of mAbs to the N protein were assessed for cross-reactivity with the SARS-CoV and Middle East respiratory syndrome (MERS)-CoV N proteins and could be subdivided into sets that showed unique specificity for SARS-CoV-2 N protein, cross-reactivity between SARS-CoV-2 and SARS-CoV N proteins only, or cross-reactivity to all three coronavirus N proteins tested. Partial mapping of N-reactive mAbs were conducted using truncated fragments of the SARS-CoV-2 N protein and revealed near complete coverage of the N protein. Collectively, these sets of mouse and rabbit monoclonal antibodies can be used to examine structure/function studies for N proteins and to define the surface location of virus neutralizing epitopes on the RBD of the S protein.


Subject(s)
Betacoronavirus/immunology , Coronavirus Nucleocapsid Proteins/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Binding Sites/immunology , COVID-19/immunology , Coronavirus Nucleocapsid Proteins/metabolism , Cross Reactions , Epitopes/metabolism , Humans , Mice , Neutralization Tests , Phosphoproteins/immunology , Phosphoproteins/metabolism , Protein Binding/immunology , Rabbits , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Viral Envelope Proteins/metabolism
14.
Immunity ; 54(10): 2385-2398.e10, 2021 10 12.
Article in English | MEDLINE | ID: mdl-34508662

ABSTRACT

Potent neutralizing SARS-CoV-2 antibodies often target the spike protein receptor-binding site (RBS), but the variability of RBS epitopes hampers broad neutralization of multiple sarbecoviruses and drifted viruses. Here, using humanized mice, we identified an RBS antibody with a germline VH gene that potently neutralized SARS-related coronaviruses, including SARS-CoV and SARS-CoV-2 variants. X-ray crystallography revealed coordinated recognition by the heavy chain of non-RBS conserved sites and the light chain of RBS with a binding angle mimicking the angiotensin-converting enzyme 2 (ACE2) receptor. The minimum footprints in the hypervariable region of RBS contributed to the breadth of neutralization, which was enhanced by immunoglobulin G3 (IgG3) class switching. The coordinated binding resulted in broad neutralization of SARS-CoV and emerging SARS-CoV-2 variants of concern. Low-dose therapeutic antibody treatment in hamsters reduced the virus titers and morbidity during SARS-CoV-2 challenge. The structural basis for broad neutralizing activity may inform the design of a broad spectrum of therapeutics and vaccines.


Subject(s)
Broadly Neutralizing Antibodies/immunology , Cross Reactions/immunology , SARS-CoV-2/immunology , Animals , Betacoronavirus/immunology , Binding Sites, Antibody , Broadly Neutralizing Antibodies/chemistry , Broadly Neutralizing Antibodies/therapeutic use , COVID-19/prevention & control , COVID-19/therapy , COVID-19/virology , Cricetinae , Humans , Immunoglobulin Class Switching , Immunoglobulin Fab Fragments/chemistry , Immunoglobulin Fab Fragments/metabolism , Immunoglobulin G/chemistry , Immunoglobulin G/immunology , Mice , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
15.
Front Immunol ; 12: 696370, 2021.
Article in English | MEDLINE | ID: mdl-34386006

ABSTRACT

The COVID-19 pandemic is caused by SARS-CoV-2, a novel zoonotic coronavirus. Emerging evidence indicates that preexisting humoral immunity against other seasonal human coronaviruses (HCoVs) plays a critical role in the specific antibody response to SARS-CoV-2. However, current work to assess the effects of preexisting and cross-reactive anti-HCoVs antibodies has been limited. To address this issue, we have adapted our previously reported multiplex assay to simultaneously and quantitatively measure anti-HCoV antibodies. The full mPlex-CoV panel covers the spike (S) and nucleocapsid (N) proteins of three highly pathogenic HCoVs (SARS-CoV-1, SARS-CoV-2, MERS) and four human seasonal strains (OC43, HKU1, NL63, 229E). Combining this assay with volumetric absorptive microsampling (VAMS), we measured the anti-HCoV IgG, IgA, and IgM antibodies in fingerstick blood samples. The results demonstrate that the mPlex-CoV assay has high specificity and sensitivity. It can detect strain-specific anti-HCoV antibodies down to 0.1 ng/ml with 4 log assay range and with low intra- and inter-assay coefficients of variation (%CV). We also estimate multiple strain HCoVs IgG, IgA and IgM concentration in VAMS samples in three categories of subjects: pre-COVID-19 (n=21), post-COVID-19 convalescents (n=19), and COVID-19 vaccine recipients (n=14). Using metric multidimensional scaling (MDS) analysis, HCoVs IgG concentrations in fingerstick blood samples were well separated between the pre-COVID-19, post-COVID-19 convalescents, and COVID-19 vaccine recipients. In addition, we demonstrate how multi-dimensional scaling analysis can be used to visualize IgG mediated antibody immunity against multiple human coronaviruses. We conclude that the combination of VAMS and the mPlex-Cov assay is well suited to performing remote study sample collection under pandemic conditions to monitor HCoVs antibody responses in population studies.


Subject(s)
Antibodies, Viral/blood , Coronavirus/immunology , Cross Reactions/immunology , Immunoassay/methods , Antibodies, Viral/immunology , Betacoronavirus/immunology , COVID-19/immunology , Coronavirus 229E, Human/immunology , Coronavirus NL63, Human/immunology , Coronavirus Nucleocapsid Proteins/immunology , Coronavirus OC43, Human/immunology , Humans , Immunoglobulin A/blood , Immunoglobulin A/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/blood , Immunoglobulin M/immunology , SARS Virus/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology
16.
Science ; 373(6559): 1109-1116, 2021 Sep 03.
Article in English | MEDLINE | ID: mdl-34344823

ABSTRACT

The spillovers of betacoronaviruses in humans and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight the need for broad coronavirus countermeasures. We describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple betacoronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies, we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through the inhibition of membrane fusion, and we delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity, and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-betacoronavirus vaccines eliciting broad protection.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Betacoronavirus/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Viral Vaccines/immunology , Virus Internalization , Animals , Antibodies, Monoclonal/isolation & purification , Antibodies, Neutralizing/isolation & purification , Convalescence , Cricetinae , Cross Reactions , Humans , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fc Fragments/immunology , Jurkat Cells , Lung/immunology , Membrane Fusion/immunology , Neutralization Tests , Peptide Mapping , Protein Conformation, alpha-Helical , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Viral Load/immunology
17.
Arch Pathol Lab Med ; 145(10): 1194-1211, 2021 10 01.
Article in English | MEDLINE | ID: mdl-34232978

ABSTRACT

CONTEXT.­: The purpose of this review was to compare 3 coronavirus diseases, including severe acute respiratory syndrome, Middle East respiratory syndrome, and COVID-19 caused by SARS-CoV, MERS-CoV, and SARS-CoV-2 viruses, respectively. OBJECTIVE.­: To cover the following topics: clinical considerations, viral characteristics, pathology, immune response, pathogenesis, and the prognosis associated with each coronavirus disease in humans. DATA SOURCES.­: Clinically, flu-like symptoms are usual at the time of presentation for all 3 diseases, but these vary from asymptomatic to severe multisystem involvement. The pathology associated with symptomatic severe acute respiratory syndrome and COVID-19 has been well described, the most prominent of which is diffuse alveolar damage. The immune response to each of these viruses is highly complex and includes both humoral and cellular components that can have a significant impact on prognosis. In severe cases of COVID-19, a dysregulated innate host immune system can initiate a hyperinflammatory syndrome dominated by endothelial dysfunction that can lead to a hypercoagulable state with microthrombi, resulting in a systemic microvascular and macrovascular disease. CONCLUSIONS.­: The severe acute respiratory syndrome and Middle East respiratory syndrome epidemics have been limited, involving approximately 8000 and 2500 individuals, respectively. In contrast, COVID-19 has resulted in a worldwide pandemic with more than 177 million cases and 3.9 million deaths as of June 15, 2021, and fatality rates ranging from less than 0.1% to approximately 10% depending upon the country. Ending on a positive note, the development of a number of vaccines, at least 6 of which now are in clinical use, should mitigate and eventually control the devastating COVID-19 pandemic.


Subject(s)
COVID-19/immunology , Coronavirus Infections/immunology , Immune System/immunology , Severe Acute Respiratory Syndrome/immunology , Betacoronavirus/immunology , Betacoronavirus/physiology , COVID-19/epidemiology , COVID-19/virology , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Humans , Pandemics/prevention & control , Prognosis , SARS Virus/immunology , SARS Virus/physiology , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/virology
18.
JCI Insight ; 6(16)2021 08 23.
Article in English | MEDLINE | ID: mdl-34237028

ABSTRACT

Some studies suggest that recent common coronavirus (CCV) infections are associated with reduced COVID-19 severity upon SARS-CoV-2 infection. We completed serological assays using samples collected from health care workers to identify antibody types associated with SARS-CoV-2 protection and COVID-19 symptom duration. Rare SARS-CoV-2 cross-reactive antibodies elicited by past CCV infections were not associated with protection; however, the duration of symptoms following SARS-CoV-2 infections was significantly reduced in individuals with higher common betacoronavirus (ßCoV) antibody titers. Since antibody titers decline over time after CCV infections, individuals in our cohort with higher ßCoV antibody titers were more likely recently infected with common ßCoVs compared with individuals with lower antibody titers. Therefore, our data suggest that recent ßCoV infections potentially limit the duration of symptoms following SARS-CoV-2 infections through mechanisms that do not involve cross-reactive antibodies. Our data are consistent with the emerging hypothesis that cellular immune responses elicited by recent common ßCoV infections transiently reduce symptom duration following SARS-CoV-2 infections.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/immunology , COVID-19/immunology , Health Personnel , SARS-CoV-2/immunology , Adult , Cross Reactions , Female , Humans , Male , Middle Aged , Time Factors
19.
Science ; 373(6558): 991-998, 2021 08 27.
Article in English | MEDLINE | ID: mdl-34214046

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and SARS-CoV-2 in 2019 highlights the need to develop universal vaccination strategies against the broader Sarbecovirus subgenus. Using chimeric spike designs, we demonstrate protection against challenge from SARS-CoV, SARS-CoV-2, SARS-CoV-2 B.1.351, bat CoV (Bt-CoV) RsSHC014, and a heterologous Bt-CoV WIV-1 in vulnerable aged mice. Chimeric spike messenger RNAs (mRNAs) induced high levels of broadly protective neutralizing antibodies against high-risk Sarbecoviruses. By contrast, SARS-CoV-2 mRNA vaccination not only showed a marked reduction in neutralizing titers against heterologous Sarbecoviruses, but SARS-CoV and WIV-1 challenge in mice resulted in breakthrough infections. Chimeric spike mRNA vaccines efficiently neutralized D614G, mink cluster five, and the UK B.1.1.7 and South African B.1.351 variants of concern. Thus, multiplexed-chimeric spikes can prevent SARS-like zoonotic coronavirus infections with pandemic potential.


Subject(s)
Betacoronavirus/immunology , COVID-19 Vaccines/immunology , Coronavirus Infections/prevention & control , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/immunology , Viral Vaccines/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Betacoronavirus/physiology , COVID-19/prevention & control , Coronavirus Infections/immunology , Cross Protection , Cytokines/blood , Female , Immunity, Heterologous , Immunogenicity, Vaccine , Liposomes , Lung/pathology , Lung/virology , Mice , Mice, Inbred BALB C , Nanoparticles , Protein Domains , Recombinant Fusion Proteins , SARS Virus/immunology , SARS Virus/physiology , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/prevention & control , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Virus Replication
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