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1.
Elife ; 112022 10 27.
Article in English | MEDLINE | ID: covidwho-2164143

ABSTRACT

Background: HIV infection dysregulates the B cell compartment, affecting memory B cell formation and the antibody response to infection and vaccination. Understanding the B cell response to SARS-CoV-2 in people living with HIV (PLWH) may explain the increased morbidity, reduced vaccine efficacy, reduced clearance, and intra-host evolution of SARS-CoV-2 observed in some HIV-1 coinfections. Methods: We compared B cell responses to COVID-19 in PLWH and HIV negative (HIV-ve) patients in a cohort recruited in Durban, South Africa, during the first pandemic wave in July 2020 using detailed flow cytometry phenotyping of longitudinal samples with markers of B cell maturation, homing, and regulatory features. Results: This revealed a coordinated B cell response to COVID-19 that differed significantly between HIV-ve and PLWH. Memory B cells in PLWH displayed evidence of reduced germinal centre (GC) activity, homing capacity, and class-switching responses, with increased PD-L1 expression, and decreased Tfh frequency. This was mirrored by increased extrafollicular (EF) activity, with dynamic changes in activated double negative (DN2) and activated naïve B cells, which correlated with anti-RBD-titres in these individuals. An elevated SARS-CoV-2-specific EF response in PLWH was confirmed using viral spike and RBD bait proteins. Conclusions: Despite similar disease severity, these trends were highest in participants with uncontrolled HIV, implicating HIV in driving these changes. EF B cell responses are rapid but give rise to lower affinity antibodies, less durable long-term memory, and reduced capacity to adapt to new variants. Further work is needed to determine the long-term effects of HIV on SARS-CoV-2 immunity, particularly as new variants emerge. Funding: This work was supported by a grant from the Wellcome Trust to the Africa Health Research Institute (Wellcome Trust Strategic Core Award [grant number 201433/Z/16/Z]). Additional funding was received from the South African Department of Science and Innovation through the National Research Foundation (South African Research Chairs Initiative [grant number 64809]), and the Victor Daitz Foundation.


Subject(s)
COVID-19 , HIV Infections , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , South Africa , Antibodies, Viral
2.
Transpl Int ; 35: 10721, 2022.
Article in English | MEDLINE | ID: covidwho-2154859

ABSTRACT

Kidney transplant recipients (KTR) are at increased risk for COVID-19-associated complications. We aimed to describe the evolving epidemiology and outcome of PCR-documented SARS-CoV-2 infection in KTR followed at our institution from March 2020 to May 2022. The primary endpoint was hospitalization for COVID-19-related symptoms or death within 28 days from diagnosis. Overall, 243 cases were included of which 68 (28%) developed the primary outcome. A significant decrease in the incidence of the primary outcome was observed (p < 0.001, r -0.342) during the study period. Anti-Spike monoclonal antibodies (mAbs) were administered as early treatment (within 5-7 days of onset of symptoms) in 101 patients (14 with casirivimab/imdevimab and 87 with sotrovimab). Among 145 patients who had received at least one vaccination dose before infection, 109 patients were considered as adequately vaccinated. Multivariate analysis revealed that the Charlson Comorbidity Index (P 0.001; OR 1.28, CI 1.11-1.48) was associated with the primary outcome, while early administration of mAbs (P 0.032; OR 0.39, CI 0.16-0.92) was associated with a better outcome, but not infection during the period of the omicron variant predominance or adequate vaccination.


Subject(s)
COVID-19 , Kidney Transplantation , Humans , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Transplant Recipients
3.
Viruses ; 14(10)2022 10 14.
Article in English | MEDLINE | ID: covidwho-2143679

ABSTRACT

For more than two years after the emergence of COVID-19 (Coronavirus Disease-2019), significant regional differences in morbidity persist. These differences clearly show lower incidence rates in several regions of the African and Asian continents. The work reported here aimed to test the hypothesis of a pre-pandemic natural immunity acquired by some human populations in central and western Africa, which would, therefore, pose the hypothesis of an original antigenic sin with a virus antigenically close to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). To identify such pre-existing immunity, sera samples collected before the emergence of COVID-19 were tested to detect the presence of IgG reacting antibodies against SARS-CoV-2 proteins of major significance. Sera samples from French blood donors collected before the pandemic served as a control. The results showed a statistically significant difference of antibodies prevalence between the collected samples in Africa and the control samples collected in France. Given the novelty of our results, our next step consists in highlighting neutralizing antibodies to evaluate their potential for pre-pandemic protective acquired immunity against SARS-CoV-2. In conclusion, our results suggest that, in the investigated African sub-regions, the tested populations could have been potentially and partially pre-exposed, before the COVID-19 pandemic, to the antigens of a yet non-identified Coronaviruses.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Pandemics , COVID-19/epidemiology , Spike Glycoprotein, Coronavirus , Antibodies, Neutralizing , Immunoglobulin G , Antibodies, Viral
4.
Viruses ; 14(9)2022 09 14.
Article in English | MEDLINE | ID: covidwho-2143631

ABSTRACT

In this retrospective, single-center study, we conducted an analysis of 13,699 samples from different individuals obtained from the Federal Research Center of Fundamental and Translational Medicine, from 1 April to 30 May 2020 in Novosibirsk region (population 2.8 million people). We identified 6.49% positive for SARS-CoV-2 cases out of the total number of diagnostic tests, and 42% of them were from asymptomatic people. We also detected two asymptomatic people, who had no confirmed contact with patients with COVID-19. The highest percentage of positive samples was observed in the 80+ group (16.3%), while among the children and adults it did not exceed 8%. Among all the people tested, 2423 came from a total of 80 different destinations and only 27 of them were positive for SARS-CoV-2. Out of all the positive samples, 15 were taken for SARS-CoV-2 sequencing. According to the analysis of the genome sequences, the SARS-CoV-2 variants isolated in the Novosibirsk region at the beginning of the pandemic belonged to three phylogenetic lineages according to the Pangolin classification: B.1, B.1.1, and B.1.1.129. All Novosibirsk isolates contained the D614G substitution in the Spike protein, two isolates werecharacterized by an additional M153T mutation, and one isolate wascharacterized by the L5F mutation.


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , COVID-19/epidemiology , Child , Genome, Viral , Genomics , Humans , Mutation , Pandemics , Phylogeny , Retrospective Studies , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
5.
Front Immunol ; 13: 981693, 2022.
Article in English | MEDLINE | ID: covidwho-2142011

ABSTRACT

Objectives: Emergence of new variants of SARS-CoV-2 might affect vaccine efficacy. Therefore, assessing the capacity of sera to neutralize variants of concern (VOCs) in BSL-2 conditions will help evaluating the immune status of population following vaccination or infection. Methods: Pseudotyped viruses bearing SARS-CoV-2 spike protein from Wuhan-Hu-1/D614G strains (wild type, WT), B.1.617.2 (Delta), or B.1.1.529 (Omicron) VOCs were generated to assess the neutralizing antibodies (nAbs) activity by a pseudovirus-based neutralization assay (PVNA). PVNA performance was assessed in comparison to the micro-neutralization test (MNT) based on live viruses. Sera collected from COVID-19 convalescents and vaccinees receiving mRNA (BNT16b2 or mRNA-1273) or viral vector (AZD1222 or Ad26.COV2.S) vaccines were used to measure nAbs elicited by two-dose BNT16b2, mRNA-1273, AZD1222 or one-dose Ad26.CO2.S, at different times from completed vaccination, ~ 1.5 month and ~ 4-6 months. Sera from pre-pandemic and unvaccinated individuals were analyzed as controls. Neutralizing activity following booster vaccinations against VOCs was also determined. Results: PVNA titers correlated with the gold standard MNT assay, validating the reliability of PVNA. Sera analyzed late from the second dose showed a reduced neutralization activity compared to sera collected earlier. Ad26.CO2.S vaccination led to very low or absent nAbs. Neutralization of Delta and Omicron BA.1 VOCs showed significant reduction of nAbs respect to WT strain. Importantly, booster doses enhanced Omicron BA.1 nAbs, with persistent levels at 3 months from boosting. Conclusions: PVNA is a reliable tool for assessing anti-SARS-CoV-2 nAbs helping the establishment of a correlate of protection and the management of vaccination strategies.


Subject(s)
COVID-19 , RNA Viruses , Ad26COVS1 , Antibodies, Neutralizing , COVID-19/prevention & control , Carbon Dioxide , ChAdOx1 nCoV-19 , Humans , Membrane Glycoproteins/metabolism , RNA, Messenger , Reproducibility of Results , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus , Viral Envelope Proteins
6.
Front Immunol ; 13: 946318, 2022.
Article in English | MEDLINE | ID: covidwho-2141971

ABSTRACT

Background and Methods: The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Omicron (B.1.1.529) variant is the antigenically most distinct variant to date. As the heavily mutated spike protein enables neutralization escape, we studied serum-neutralizing activities of naïve and vaccinated individuals after Omicron BA.1 or BA.2 sub-lineage infections in live virus neutralization tests with Omicron BA.1, Omicron BA.2, wildtype (WT, B1.1), and Delta (B.1.617.2) strains. Serum samples obtained after WT infections and three-dose mRNA vaccinations with and without prior infection were included as controls. Results: Primary BA.1 infections yielded reduced neutralizing antibody levels against WT, Delta, and Omicron BA.2, while samples from BA.2-infected individuals showed almost no cross-neutralization against the other variants. Serum neutralization of Omicron BA.1 and BA.2 variants was detectable after three-dose mRNA vaccinations, but with reduced titers. Vaccination-breakthrough infections with either Omicron BA.1 or BA.2, however, generated equal cross-neutralizing antibody levels against all SARS-CoV-2 variants tested. Conclusions: Our study demonstrates that although Omicron variants are able to enhance cross-neutralizing antibody levels in pre-immune individuals, primary infections with BA.1 or BA.2 induced mostly variant-specific neutralizing antibodies, emphasizing the differently shaped humoral immunity induced by the two Omicron variants. These data thus contribute substantially to the understanding of antibody responses induced by primary Omicron infections or multiple exposures to different SARS-CoV-2 variants and are of particular importance for developing vaccination strategies in the light of future emerging variants.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , Broadly Neutralizing Antibodies , Humans , Membrane Glycoproteins , Neutralization Tests , RNA, Messenger , Spike Glycoprotein, Coronavirus/genetics , Viral Envelope Proteins
7.
Front Immunol ; 13: 938378, 2022.
Article in English | MEDLINE | ID: covidwho-2141954

ABSTRACT

Background: SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has infected millions of people around the world. Vaccination is a pillar in the strategy to control transmission of the SARS-CoV-2 spread. Immune responses to vaccination require elucidation. Methods: The immune responses to vaccination with three doses of inactivated SARS-CoV-2 vaccine were followed in a cohort of 37 healthy adults (18-59 years old). Blood samples were collected at multiple time points and submitted to peptide array, machine learning modeling, and sequence alignment analyses, the results of which were used to generate vaccine-induced antibody-binding region (VIABR) immunosignatures (Registration number: ChiCTR2200058571). Results: Antibody spectrum signals showed vaccination stimulated antibody production. Sequence alignment analyses revealed that a third vaccine dose generated a new highly represented VIABR near the A570D mutation, and the whole process of inoculation enhanced the VIABR near the N501Y mutation. In addition, the antigen conformational epitopes varied between short- and long-term samples. The amino acids with the highest scores in the short-term samples were distributed primarily in the receptor binding domain (RBD) and N-terminal domain regions of spike (S) protein, while in the long-term samples (12 weeks after the 2nd dose), some new conformational epitopes (CEs) were localized to crevices within the head of the S protein trimer. Conclusion: Protective antigenic epitopes were revealed by immunosignatures after three doses of inactivated SARS-CoV-2 vaccine inoculation. A third dose results in a new top-10 VIABR near the A570D mutation site of S protein, and the whole process of inoculation enhanced the VIABR near the N501Y mutation, thus potentially providing protection from strains that have gained invasion and immune escape abilities through these mutation.


Subject(s)
COVID-19 , Viral Vaccines , Adolescent , Adult , COVID-19/prevention & control , COVID-19 Vaccines , Epitopes , Humans , Middle Aged , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Young Adult
8.
Front Immunol ; 13: 838780, 2022.
Article in English | MEDLINE | ID: covidwho-2141804

ABSTRACT

Antibodies specific for the spike glycoprotein (S) and nucleocapsid (N) SARS-CoV-2 proteins are typically present during severe COVID-19, and induced to S after vaccination. The binding of viral antigens by antibody can initiate the classical complement pathway. Since complement could play pathological or protective roles at distinct times during SARS-CoV-2 infection we determined levels of antibody-dependent complement activation along the complement cascade. Here, we used an ELISA assay to assess complement protein binding (C1q) and the deposition of C4b, C3b, and C5b to S and N antigens in the presence of antibodies to SARS-CoV-2 from different test groups: non-infected, single and double vaccinees, non-hospitalised convalescent (NHC) COVID-19 patients and convalescent hospitalised (ITU-CONV) COVID-19 patients. C1q binding correlates strongly with antibody responses, especially IgG1 levels. However, detection of downstream complement components, C4b, C3b and C5b shows some variability associated with the subject group from whom the sera were obtained. In the ITU-CONV, detection of C3b-C5b to S was observed consistently, but this was not the case in the NHC group. This is in contrast to responses to N, where median levels of complement deposition did not differ between the NHC and ITU-CONV groups. Moreover, for S but not N, downstream complement components were only detected in sera with higher IgG1 levels. Therefore, the classical pathway is activated by antibodies to multiple SARS-CoV-2 antigens, but the downstream effects of this activation may differ depending the disease status of the subject and on the specific antigen targeted.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Complement Activation , Complement C1q , Humans , Immunoglobulin G , Nucleoproteins , Spike Glycoprotein, Coronavirus , Vaccination
9.
PLoS Pathog ; 18(11): e1010951, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2140720

ABSTRACT

SARS-CoV-2 continues to acquire mutations in the spike receptor-binding domain (RBD) that impact ACE2 receptor binding, folding stability, and antibody recognition. Deep mutational scanning prospectively characterizes the impacts of mutations on these biochemical properties, enabling rapid assessment of new mutations seen during viral surveillance. However, the effects of mutations can change as the virus evolves, requiring updated deep mutational scans. We determined the impacts of all single amino acid mutations in the Omicron BA.1 and BA.2 RBDs on ACE2-binding affinity, RBD folding, and escape from binding by the LY-CoV1404 (bebtelovimab) monoclonal antibody. The effects of some mutations in Omicron RBDs differ from those measured in the ancestral Wuhan-Hu-1 background. These epistatic shifts largely resemble those previously seen in the Alpha variant due to the convergent epistatically modifying N501Y substitution. However, Omicron variants show additional lineage-specific shifts, including examples of the epistatic phenomenon of entrenchment that causes the Q498R and N501Y substitutions present in Omicron to be more favorable in that background than in earlier viral strains. In contrast, the Omicron substitution Q493R exhibits no sign of entrenchment, with the derived state, R493, being as unfavorable for ACE2 binding in Omicron RBDs as in Wuhan-Hu-1. Likely for this reason, the R493Q reversion has occurred in Omicron sub-variants including BA.4/BA.5 and BA.2.75, where the affinity buffer from R493Q reversion may potentiate concurrent antigenic change. Consistent with prior studies, we find that Omicron RBDs have reduced expression, and identify candidate stabilizing mutations that ameliorate this deficit. Last, our maps highlight a broadening of the sites of escape from LY-CoV1404 antibody binding in BA.1 and BA.2 compared to the ancestral Wuhan-Hu-1 background. These BA.1 and BA.2 deep mutational scanning datasets identify shifts in the RBD mutational landscape and inform ongoing efforts in viral surveillance.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Humans , Angiotensin-Converting Enzyme 2/genetics , Spike Glycoprotein, Coronavirus , SARS-CoV-2/genetics , COVID-19/genetics , Antibodies, Neutralizing/chemistry , Mutation
10.
PLoS One ; 17(6): e0267796, 2022.
Article in English | MEDLINE | ID: covidwho-2140390

ABSTRACT

The current global COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a public health crisis with more than 168 million cases reported globally and more than 4.5 million deaths at the time of writing. In addition to the direct impact of the disease, the economic impact has been significant as public health measures to contain or reduce the spread have led to country wide lockdowns resulting in near closure of many sectors of the economy. Antibodies are a principal determinant of the humoral immune response to COVID-19 infections and may have the potential to reduce disease and spread of the virus. The development of monoclonal antibodies (mAbs) represents a therapeutic option that can be produced at large quantity and high quality. In the present study, a mAb combination mixture therapy was investigated for its capability to specifically neutralize SARS-CoV-2. We demonstrate that each of the antibodies bind the spike protein and neutralize the virus, preventing it from infecting cells in an in vitro cell-based assay, including multiple viral variants that are currently circulating in the human population. In addition, we investigated the effects of two different mutations in the Fc portion (YTE and LALA) of the antibody on Fc effector function and the ability to alleviate potential antibody-dependent enhancement of disease. These data demonstrate the potential of a combination of two mAbs that target two different epitopes on the SARS-CoV2 spike protein to provide protection against SARS-CoV-2 infection in humans while extending serum half-life and preventing antibody-dependent enhancement of disease.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing , Antibodies, Viral/therapeutic use , COVID-19/drug therapy , Communicable Disease Control , Humans , Pandemics , RNA, Viral , Spike Glycoprotein, Coronavirus
11.
J Biomed Sci ; 29(1): 37, 2022 Jun 09.
Article in English | MEDLINE | ID: covidwho-2139298

ABSTRACT

BACKGROUND: Calls for the coronavirus to be treated as an endemic illness, such as the flu, are increasing. After achieving high coverage of COVID-19 vaccination, therapeutic drugs have become important for future SARS-CoV-2 variant outbreaks. Although many monoclonal antibodies have been approved for emergency use as treatments for SARS-CoV-2 infection, some monoclonal antibodies are not authorized for variant treatment. Broad-spectrum monoclonal antibodies are unmet medical needs. METHODS: We used a DNA prime-protein boost approach to generate high-quality monoclonal antibodies. A standard ELISA was employed for the primary screen, and spike protein-human angiotensin-converting enzyme 2 blocking assays were used for the secondary screen. The top 5 blocking clones were selected for further characterization, including binding ability, neutralization potency, and epitope mapping. The therapeutic effects of the best monoclonal antibody against SARS-CoV-2 infection were evaluated in a hamster infection model. RESULTS: Several monoclonal antibodies were selected that neutralize different SARS-CoV-2 variants of concern (VOCs). These VOCs include Alpha, Beta, Gamma, Delta, Kappa and Lambda variants. The high neutralizing antibody titers against the Beta variant would be important to treat Beta-like variants. Among these monoclonal antibodies, mAb-S5 displays the best potency in terms of binding affinity and neutralizing capacity. Importantly, mAb-S5 protects animals from SARS-CoV-2 challenge, including the Wuhan strain, D614G, Alpha and Delta variants, although mAb-S5 exhibits decreased neutralization potency against the Delta variant. Furthermore, the identified neutralizing epitopes of monoclonal antibodies are all located in the receptor-binding domain (RBD) of the spike protein but in different regions. CONCLUSIONS: Our approach generates high-potency monoclonal antibodies against a broad spectrum of VOCs. Multiple monoclonal antibody combinations may be the best strategy to treat future SARS-CoV-2 variant outbreaks.


Subject(s)
Antibodies, Monoclonal , COVID-19 , SARS-CoV-2 , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , COVID-19/drug therapy , COVID-19 Vaccines , Cricetinae , Humans , Spike Glycoprotein, Coronavirus/genetics
12.
Dis Markers ; 2022: 1118195, 2022.
Article in English | MEDLINE | ID: covidwho-2138216

ABSTRACT

Background: Mitochondria have been involved in host defense upon viral infections. Factor Xa (FXa), a coagulating factor, may also have influence on mitochondrial functionalities. The aim was to analyze if in human pulmonary microvascular endothelial cells (HPMEC), the SARS-CoV-2 (COVID-19) spike protein subunits, S1 and S2 (S1+S2), could alter mitochondrial metabolism and what is the role of FXA. Methods: HPMEC were incubated with and without recombinants S1+S2 (10 nmol/L each). Results: In control conditions, S1+S2 failed to modify FXa expression. However, in LPS (1 µg/mL)-incubated HPMEC, S1+S2 significantly increased FXa production. LPS tended to reduce mitochondrial membrane potential with respect to control, but in higher and significant degree, it was reduced when S1+S2 were present. LPS did not significantly modify cytochrome c oxidase activity as compared with control. Addition of S1+S2 spike subunits to LPS-incubated HPMEC significantly increased cytochrome c oxidase activity with respect to control. Lactate dehydrogenase activity was also increased by S1+S2 with respect to control and LPS alone. Protein expression level of uncoupled protein-2 (UCP-2) was markedly expressed when S1+S2 were added together to LPS. Rivaroxaban (50 nmol/L), a specific FXa inhibitor, significantly reduced all the above-mentioned alterations induced by S1+S2 including UCP-2 expression. Conclusions: In HPMEC undergoing to preinflammatory condition, COVID-19 S1+S2 spike subunits promoted alterations in mitochondria metabolism suggesting a shift from aerobic towards anaerobic metabolism that was accompanied of high FXa production. Rivaroxaban prevented all the mitochondrial metabolic changes mediated by the present COVID-19 S1 and S2 spike subunits suggesting the involvement of endogenous FXa.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Humans , Spike Glycoprotein, Coronavirus/metabolism , Factor Xa/metabolism , SARS-CoV-2 , Endothelial Cells/metabolism , Protein Subunits/metabolism , Rivaroxaban/pharmacology , Rivaroxaban/metabolism , Electron Transport Complex IV/metabolism , Lipopolysaccharides/pharmacology , Lipopolysaccharides/metabolism , Mitochondria/metabolism
13.
Sci Adv ; 8(47): eadc9179, 2022 11 25.
Article in English | MEDLINE | ID: covidwho-2137353

ABSTRACT

As coronavirus disease 2019 (COVID-19) persists, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) emerge, accumulating spike (S) glycoprotein mutations. S receptor binding domain (RBD) comprises a free fatty acid (FFA)-binding pocket. FFA binding stabilizes a locked S conformation, interfering with virus infectivity. We provide evidence that the pocket is conserved in pathogenic ß-coronaviruses (ß-CoVs) infecting humans. SARS-CoV, MERS-CoV, SARS-CoV-2, and VOCs bind the essential FFA linoleic acid (LA), while binding is abolished by one mutation in common cold-causing HCoV-HKU1. In the SARS-CoV S structure, LA stabilizes the locked conformation, while the open, infectious conformation is devoid of LA. Electron tomography of SARS-CoV-2-infected cells reveals that LA treatment inhibits viral replication, resulting in fewer deformed virions. Our results establish FFA binding as a hallmark of pathogenic ß-CoV infection and replication, setting the stage for FFA-based antiviral strategies to overcome COVID-19.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Humans , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Fatty Acids, Nonesterified , SARS-CoV-2
14.
J Infect Dis ; 226(11): 1909-1912, 2022 Nov 28.
Article in English | MEDLINE | ID: covidwho-2135323

ABSTRACT

We investigated antibody titers and avidity after heterologous versus homologous coronavirus disease 2019 vaccination over 6 months after the second dose. We found a significantly higher avidity in regimens including at least 1 dose of the adenoviral vector vaccine ChAdOx1-S compared with 2 doses of the mRNA vaccine BNT162b2.


Subject(s)
COVID-19 , Viral Vaccines , Humans , Antibody Affinity , Kinetics , COVID-19/prevention & control , BNT162 Vaccine , Vaccination , Adenoviridae , Spike Glycoprotein, Coronavirus/genetics
15.
J Infect Dis ; 226(11): 1897-1902, 2022 Nov 28.
Article in English | MEDLINE | ID: covidwho-2135321

ABSTRACT

BACKGROUND: The consequences of past coronavirus disease 2019 (COVID-19) infection for personal and population health are emerging, but accurately identifying distant infection is a challenge. Anti-spike antibodies rise after both vaccination and infection and anti-nucleocapsid antibodies rapidly decline. METHODS: We evaluated anti-membrane antibodies in COVID-19 naive, vaccinated, and convalescent subjects to determine if they persist and accurately detect distant infection. RESULTS: We found that anti-membrane antibodies persist for at least 1 year and are a sensitive and specific marker of past COVID-19 infection. CONCLUSIONS: Thus, anti-membrane and anti-spike antibodies together can differentiate between COVID-19 convalescent, vaccinated, and naive states to advance public health and research.


Subject(s)
COVID-19 , Humans , COVID-19/diagnosis , Vaccination , Public Health , Virion , Antibodies, Viral , Spike Glycoprotein, Coronavirus
16.
Commun Biol ; 5(1): 1179, 2022 Nov 04.
Article in English | MEDLINE | ID: covidwho-2133651

ABSTRACT

Understanding the antigenic signatures of all human coronaviruses (HCoVs) Spike (S) proteins is imperative for pan-HCoV epitopes identification and broadly effective vaccine development. To depict the currently elusive antigenic signatures of α-HCoVs S proteins, we isolated a panel of antibodies against the HCoV-229E S protein and characterized their epitopes and neutralizing potential. We found that the N-terminal domain of HCoV-229E S protein is antigenically dominant wherein an antigenic supersite is present and appears conserved in HCoV-NL63, which holds potential to serve as a pan-α-HCoVs epitope. In the receptor binding domain, a neutralizing epitope is captured in the end distal to the receptor binding site, reminiscent of the locations of the SARS-CoV-2 RBD cryptic epitopes. We also identified a neutralizing antibody that recognizes the connector domain, thus representing the first S2-directed neutralizing antibody against α-HCoVs. The unraveled HCoVs S proteins antigenic similarities and variances among genera highlight the challenges faced by pan-HCoV vaccine design while supporting the feasibility of broadly effective vaccine development against a subset of HCoVs.


Subject(s)
COVID-19 , Coronavirus 229E, Human , Humans , Spike Glycoprotein, Coronavirus/genetics , SARS-CoV-2 , Antigens, Viral , Epitopes , Antibodies, Neutralizing
17.
Sci Rep ; 12(1): 20120, 2022 Nov 22.
Article in English | MEDLINE | ID: covidwho-2133636

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). Variants of concern (VOCs) such as Delta and Omicron have developed, which continue to spread the pandemic. It has been reported that these VOCs reduce vaccine efficacy and evade many neutralizing monoclonal antibodies (mAbs) that target the receptor binding domain (RBD) of the glycosylated spike (S) protein, which consists of the S1 and S2 subunits. Therefore, identification of optimal target regions is required to obtain neutralizing antibodies that can counter VOCs. Such regions have not been identified to date. We obtained 2 mAbs, NIBIC-71 and 7G7, using peripheral blood mononuclear cells derived from volunteers who recovered from COVID-19. Both mAbs had neutralizing activity against wild-type SARS-CoV-2 and Delta, but not Omicron. NIBIC-71 binds to the RBD, whereas 7G7 recognizes the N-terminal domain of the S1. In particular, 7G7 inhibited S1/S2 cleavage but not the interaction between the S protein and angiotensin-converting enzyme 2; it suppressed viral entry. Thus, the efficacy of a neutralizing mAb targeting inhibition of S1/2 cleavage was demonstrated. These results suggest that neutralizing mAbs targeting blockade of S1/S2 cleavage are likely to be cross-reactive against various VOCs.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Humans , Spike Glycoprotein, Coronavirus/chemistry , Leukocytes, Mononuclear , Antibodies, Viral , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Monoclonal
18.
Cell Host Microbe ; 30(11): 1540-1555.e15, 2022 11 09.
Article in English | MEDLINE | ID: covidwho-2130372

ABSTRACT

The SARS-CoV-2 Omicron BA.2.75 variant emerged in May 2022. BA.2.75 is a BA.2 descendant but is phylogenetically distinct from BA.5, the currently predominant BA.2 descendant. Here, we show that BA.2.75 has a greater effective reproduction number and different immunogenicity profile than BA.5. We determined the sensitivity of BA.2.75 to vaccinee and convalescent sera as well as a panel of clinically available antiviral drugs and antibodies. Antiviral drugs largely retained potency, but antibody sensitivity varied depending on several key BA.2.75-specific substitutions. The BA.2.75 spike exhibited a profoundly higher affinity for its human receptor, ACE2. Additionally, the fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were greater than those of BA.2. Our multilevel investigations suggest that BA.2.75 acquired virological properties independent of BA.5, and the potential risk of BA.2.75 to global health is greater than that of BA.5.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Antibodies, Neutralizing , Antibodies, Viral , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
19.
Antiviral Res ; 208: 105428, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2129937

ABSTRACT

The continuous emergence of SARS-CoV-2 variants prolongs COVID-19 pandemic. Although SARS-CoV-2 vaccines and therapeutics are currently available, there is still a need for development of safe and effective drugs against SARS-CoV-2 and also for preparedness for the next pandemic. Here, we discover that astersaponin I (AI), a triterpenoid saponin in Aster koraiensis inhibits SARS-CoV-2 entry pathways at the plasma membrane and within the endosomal compartments mainly by increasing cholesterol content in the plasma membrane and interfering with the fusion of SARS-CoV-2 envelope with the host cell membrane. Moreover, we find that this functional property of AI as a fusion blocker enables it to inhibit the infection with SARS-CoV-2 variants including the Alpha, Beta, Delta, and Omicron with a similar efficacy, and the formation of syncytium, a multinucleated cells driven by SARS-CoV-2 spike protein-mediated cell-to-cell fusion. Finally, we claim that the triterpene backbone as well as the attached hydrophilic sugar moieties of AI are structurally important for its inhibitory activity against the membrane fusion event. Overall, this study demonstrates that AI is a natural viral fusion inhibitor and proposes that it can be a broad-spectrum antiviral agent against current COVID-19 pandemic and future outbreaks of novel viral pathogens.


Subject(s)
COVID-19 , SARS-CoV-2 , Saponins , Humans , COVID-19/drug therapy , COVID-19 Vaccines , Giant Cells , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Asteraceae/chemistry , Saponins/pharmacology
20.
Immun Inflamm Dis ; 10(12): e748, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2127751

ABSTRACT

INTRODUCTION: Coronavirus disease (COVID-19) is ongoing as a global epidemic and there is still a need to develop much safer and more effective new vaccines that can also be easily adapted to important variants of the pathogen. In the present study in this direction, we developed a new COVID-19 vaccine, composed of two critical antigenic fragments of the S1 and S2 region of severe acute respiratory syndrome coronavirus 2 as well as the whole nucleocapsid protein (N), which was formulated with either alum or alum plus monophosphoryl lipid A (MPLA) adjuvant combinations. METHODS: From within the spike protein S1 region, a fragmented protein P1 (MW:33 kDa) which includes the receptor-binding domain (RBD), another fragment protein P2 (MW:17.6) which contains important antigenic epitopes within the spike protein S2 region, and N protein (MW:46 kDa) were obtained after recombinant expression of the corresponding gene regions in Escherichia coli BL21. For use in immunization studies, three proteins were adsorbed with aluminum hydroxide gel and with the combination of aluminum hydroxide gel plus MPLA. RESULTS: Each of the three protein antigens produced strong reactions in enzyme-linked immunosorbent assays and Western blot analysis studies performed with convalescent COVID-19 patient sera. In mice, these combined protein vaccine candidates elicited high titer anti-P1, anti-P2, and anti-N IgG and IgG2a responses. These also induced highly neutralizing antibodies and elicited significant cell-mediated immunity as demonstrated by enhanced antigen-specific levels of interferon-γ (INF-γ) in the splenocytes of immunized mice. CONCLUSION: The results of this study showed that formulations of the three proteins with Alum or Alum + MPLA are effective in terms of humoral and cellular responses. However, since the Alum + MPLA formulation appears to be superior in Th1 response, this vaccine candidate may be recommended mainly for the elderly and immunocompromised individuals. We also believe that the alum-only formulation will provide great benefits for adults, young adolescents, and children.


Subject(s)
COVID-19 Vaccines , COVID-19 , Mice , Animals , Humans , Nucleocapsid Proteins , COVID-19/prevention & control , Aluminum Hydroxide , Spike Glycoprotein, Coronavirus/genetics , Vaccines, Subunit
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