Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 33
Filter
1.
Blood ; 138(19):754-754, 2021.
Article in English | EuropePMC | ID: covidwho-1602029

ABSTRACT

Background: Patients with hematologic conditions have a high mortality rate when infected with SARS-CoV-2 (Williamson, Nature 2020). Protection of this group from severe COVID-19 is therefore important. However, according to available vaccination guidelines, one should consider to postpone vaccination of patients on or early after chemotherapy, hematopoietic progenitor cell transplantation (HCT) or with graft versus host disease, because of anticipated poor efficacy. Based on previous (non-COVID-19) vaccination studies among hematology patients, we hypothesized that a significant group of patients may acquire sufficient protection following COVID-19 vaccination, despite disease and therapy related immunodeficiencies. Methods: We conducted a prospective cohort study with 17 cohorts of hematology patients of particular risk for severe COVID-19 who are considered to have no or limited benefit from vaccination. We evaluated humoral immune responses following 2 doses (28 days apart) of the mRNA-1273 vaccine (Moderna/Spikevax) in 722 patients, at baseline and 28 days after each vaccination as SARS-COV-2 S1- (spike)-specific serum IgG antibody concentrations by bead-based multiplex immune assay. The threshold for adequate antibody response is set at ≥300 binding antibody units (BAU)/ml according to the international WHO standard, and is associated with virus plaque reducing neutralization test titers of ≥40 PRNT 50. This study is registered as EudraCT 2021-001072-41, NL76768.029.21. Results: Patient cohorts and corresponding vaccine responses are depicted in Table 1. Vaccine efficacy, as measured by antibody concentration, 4 weeks after the 2 nd mRNA-1273 vaccination was available for 691 out of 722 participants. The majority of patients (389/691;56%) obtained an S1 antibody titer that is considered adequate (≥300 BAU/ml). Twenty-nine percent of patients (198/691) did not seroconvert (S1 antibody titer <10 BAU/ml), while the remaining 15% (104/691) did seroconvert but not to sufficient levels (10-300 BAU/ml). Adequate responses were observed in the majority of patients with sickle cell disease using hydroxyurea, chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor therapy, acute myeloid leukemia (AML) on or early after high dose chemotherapy, patients with myeloproliferative disorders on ruxolitinib, patients with multiple myeloma (MM), including those on daratumumab and those early after high-dose melphalan and autologous HCT, patients with untreated chronic lymphocytic leukemia (CLL), and patients with chronic GvHD. Insufficient or absent antibody responses were observed in the majority of AML patients receiving hypomethylating agents, CLL patients on ibrutinib, patients with B-cell non-Hodgkin's Lymphoma (NHL) during or shortly after rituximab-chemotherapy or following BEAM chemotherapy and autologous HCT, allogeneic HCT recipients <6 months after transplantation, and CAR-T cell therapy recipients. However, even in these low-responder groups considerable numbers of patients did mount sufficient antibody titers. In others, titers increased after each of both vaccinations, suggesting that booster vaccination may enhance antibody titers to sufficient levels (Figure 1). Conclusion: Vaccination with mRNA-1273 had significant efficacy in severely immunocompromised hematology patients. Adequate humoral immune responses after two dose vaccination were reached in the majority of patients receiving therapy for sickle cell disease, MPD, MM, CML and AML, in patients early after HCT and in patients with GvHD. We are currently evaluating clinical and immunologic parameters that correlate with sufficient antibody responses, pseudovirus neutralization and SARS-COV-2-specific B and T cell numbers, phenotype and function. Per study design, all participants with absent or insufficient antibody responses (<300 BAU/ml) will receive a booster vaccination 5 months after initial vaccination, and antibody responses to booster vaccinations will be presented as well. Unlike currently available guidelines, COVID-19 vaccinatio should not be postponed. Moreover, as antibody titers increased after each of both vaccinations, booster vaccination of patients with absent or insufficient antibody responses seems warranted. Figure 1 Disclosures Mutsaers:  AstraZeneca: Research Funding;BMS: Consultancy. Van Meerten:  Janssen: Consultancy;Kite, a Gilead Company: Honoraria. Kater:  BMS, Roche/Genentech: Other: Ad Board, , Research Funding;Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding;Abbvie: Honoraria, Other: Ad Board, Research Funding;Genmab, LAVA: Other: Ad Board, Steering Committee. Zweegman:  Oncopeptides: Membership on an entity's Board of Directors or advisory committees;Sanofi: Membership on an entity's Board of Directors or advisory committees;BMS: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nijhof:  Janssen: Membership on an entity's Board of Directors or advisory committees;Celgene/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

2.
Vaccines (Basel) ; 9(12)2021 Dec 14.
Article in English | MEDLINE | ID: covidwho-1572692

ABSTRACT

SARS-CoV-2-specific antibodies are secreted into human milk of infected or vaccinated lactating women and might provide protection to the breastfed infant against COVID-19. Differences in antibody response after these types of exposure are unknown. In this longitudinal cohort study, we compared the antibody response in human milk following SARS-CoV-2 vaccination or infection. We analyzed 448 human milk samples of 28 lactating women vaccinated with the SARS-CoV-2 vaccine BNT162b2 as well as 82 human milk samples of 18 lactating women with a prior SARS-CoV-2 infection. The levels of SARS-CoV-2-specific IgA in human milk were determined over a period of 70 days both after vaccination and infection. The amount of SARS-CoV-2-specific IgA in human milk was similar after SARS-CoV-2 vaccination and infection. After infection, the variability in IgA levels was higher than after vaccination. Two participants with detectable IgA prior to vaccination were analyzed separately and showed higher IgA levels following vaccination compared to both groups. In conclusion, breastfed infants of mothers who have been vaccinated with the BNT162b2 vaccine receive human milk with similar amounts of SARS-CoV-2-specific antibodies compared to infants of previously infected mothers.

3.
Cell Reports Medicine ; : 100486, 2021.
Article in English | ScienceDirect | ID: covidwho-1569129

ABSTRACT

The urgent need for, but limited availability of, SARS-CoV-2 vaccines worldwide has led to widespread consideration of dose sparing strategies. Here, we evaluate the SARS-CoV-2 specific antibody responses following BNT162b2 vaccination in 150 previously SARS-CoV-2-infected individuals from a population-based cohort. One week after first vaccine dose, spike protein antibody levels are 27-fold higher and neutralizing antibody titers 12-fold higher, exceeding titers of fully vaccinated SARS-CoV-2-naive controls, with minimal additional boosting after the second dose. Neutralizing antibody titers against four variants of concern increase after vaccination, however overall neutralization breadth does not improve. Pre-vaccination neutralizing antibody titers and time since infection have the largest positive effect on titers following vaccination. COVID-19 severity and the presence of comorbidities have no discernible impact on vaccine response. In conclusion, a single dose of BNT162b2 vaccine up to 15 months after SARS-CoV-2 infection offers higher neutralizing antibody titers than two vaccine doses in SARS-CoV-2-naive individuals.

4.
NPJ Vaccines ; 6(1): 146, 2021 Dec 03.
Article in English | MEDLINE | ID: covidwho-1550286

ABSTRACT

The emergence of SARS-CoV-2 variants that are more resistant to antibody-mediated neutralization pose a new hurdle in combating the COVID-19 pandemic. Although vaccines based on the original Wuhan sequence have been shown to be effective at preventing COVID-19, their efficacy is likely to be decreased against more neutralization-resistant variants-of-concern (VOC), in particular, the Beta variant originating in South Africa. We assessed, in mice, rabbits, and non-human primates, whether a third vaccination with experimental Wuhan-based Spike vaccines could alleviate this problem. Our data show that a third immunization improves neutralizing antibody titers against the variants-of-concern, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2). After three vaccinations, the level of neutralization against Beta was similar to the level of neutralization against the original strain after two vaccinations, suggesting that simply providing a third immunization could nullify the reduced activity of current vaccines against VOC.

5.
Elife ; 102021 11 23.
Article in English | MEDLINE | ID: covidwho-1529013

ABSTRACT

Current SARS-CoV-2 vaccines are losing efficacy against emerging variants and may not protect against future novel coronavirus outbreaks, emphasizing the need for more broadly protective vaccines. To inform the development of a pan-coronavirus vaccine, we investigated the presence and specificity of cross-reactive antibodies against the spike (S) proteins of human coronaviruses (hCoV) after SARS-CoV-2 infection and vaccination. We found an 11- to 123-fold increase in antibodies binding to SARS-CoV and MERS-CoV as well as a 2- to 4-fold difference in antibodies binding to seasonal hCoVs in COVID-19 convalescent sera compared to pre-pandemic healthy donors, with the S2 subdomain of the S protein being the main target for cross-reactivity. In addition, we detected cross-reactive antibodies to all hCoV S proteins after SARS-CoV-2 vaccination in macaques and humans, with higher responses for hCoV more closely related to SARS-CoV-2. These findings support the feasibility of and provide guidance for development of a pan-coronavirus vaccine.

6.
Preprint in English | [Unspecified Source] | ID: ppcovidwho-292779

ABSTRACT

Most antibodies isolated from COVID-19 patients are specific to SARS-CoV-2. COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here we determined a crystal structure of COVA1-16 Fab with the SARS-CoV-2 RBD, and a negative-stain EM reconstruction with the spike glycoprotein trimer, to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long CDR H3, and competes with ACE2 binding due to steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with structural and functional rationale for the epitope conservation, provide a blueprint for development of more universal SARS-like coronavirus vaccines and therapies.

7.
ACS Cent Sci ; 7(11): 1863-1873, 2021 Nov 24.
Article in English | MEDLINE | ID: covidwho-1526050

ABSTRACT

Determining how antibodies interact with the spike (S) protein of the SARS-CoV-2 virus is critical for combating COVID-19. Structural studies typically employ simplified, truncated constructs that may not fully recapitulate the behavior of the original complexes. Here, we combine two single particle mass analysis techniques (mass photometry and charge-detection mass spectrometry) to enable the measurement of full IgG binding to the trimeric SARS-CoV-2 S ectodomain. Our experiments reveal that antibodies targeting the S-trimer typically prefer stoichiometries lower than the symmetry-predicted 3:1 binding. We determine that this behavior arises from the interplay of steric clashes and avidity effects that are not reflected in common antibody constructs (i.e., Fabs). Surprisingly, these substoichiometric complexes are fully effective at blocking ACE2 binding despite containing free receptor binding sites. Our results highlight the importance of studying antibody/antigen interactions using complete, multimeric constructs and showcase the utility of single particle mass analyses in unraveling these complex interactions.

8.
Nat Commun ; 12(1): 6097, 2021 10 20.
Article in English | MEDLINE | ID: covidwho-1475295

ABSTRACT

Effective treatments against Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Monoclonal antibodies have shown promising results in patients. Here, we evaluate the in vivo prophylactic and therapeutic effect of COVA1-18, a neutralizing antibody highly potent against the B.1.1.7 isolate. In both prophylactic and therapeutic settings, SARS-CoV-2 remains undetectable in the lungs of treated hACE2 mice. Therapeutic treatment also causes a reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg-1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 shows very strong antiviral activity in the upper respiratory compartments. Using a mathematical model, we estimate that COVA1-18 reduces viral infectivity by more than 95% in these compartments, preventing lymphopenia and extensive lung lesions. Our findings demonstrate that COVA1-18 has a strong antiviral activity in three preclinical models and could be a valuable candidate for further clinical evaluation.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Neutralizing/administration & dosage , Antiviral Agents/administration & dosage , COVID-19/drug therapy , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/genetics , Animals , Antibodies, Monoclonal/pharmacokinetics , Antiviral Agents/pharmacokinetics , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Humans , Lung/metabolism , Lung/virology , Macaca fascicularis , Male , Mesocricetus , Mice , Mice, Transgenic , SARS-CoV-2/isolation & purification , Tissue Distribution , Viral Load
9.
EMBO J ; 40(20): e106765, 2021 10 18.
Article in English | MEDLINE | ID: covidwho-1436404

ABSTRACT

The current pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and outbreaks of new variants highlight the need for preventive treatments. Here, we identified heparan sulfate proteoglycans as attachment receptors for SARS-CoV-2. Notably, neutralizing antibodies against SARS-CoV-2 isolated from COVID-19 patients interfered with SARS-CoV-2 binding to heparan sulfate proteoglycans, which might be an additional mechanism of antibodies to neutralize infection. SARS-CoV-2 binding to and infection of epithelial cells was blocked by low molecular weight heparins (LMWH). Although dendritic cells (DCs) and mucosal Langerhans cells (LCs) were not infected by SARS-CoV-2, both DC subsets efficiently captured SARS-CoV-2 via heparan sulfate proteoglycans and transmitted the virus to ACE2-positive cells. Notably, human primary nasal cells were infected by SARS-CoV-2, and infection was blocked by pre-treatment with LMWH. These data strongly suggest that heparan sulfate proteoglycans are important attachment receptors facilitating infection and transmission, and support the use of LMWH as prophylaxis against SARS-CoV-2 infection.


Subject(s)
COVID-19/transmission , Heparan Sulfate Proteoglycans/metabolism , Heparin, Low-Molecular-Weight/pharmacology , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/metabolism , Antibodies, Neutralizing/pharmacology , COVID-19/drug therapy , Chlorocebus aethiops , Dendritic Cells/metabolism , Dendritic Cells/virology , Epithelial Cells/metabolism , Epithelial Cells/virology , Host-Pathogen Interactions , Humans , Mucous Membrane/cytology , Mucous Membrane/virology , SARS-CoV-2/metabolism , Syndecan-1/metabolism , Syndecan-4/metabolism , Vero Cells
10.
EBioMedicine ; 72: 103589, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1433161

ABSTRACT

BACKGROUND: To optimise the use of available SARS-CoV-2 vaccines, some advocate delaying second vaccination for individuals infected within six months. We studied whether post-vaccination immune response is equally potent in individuals infected over six months prior to vaccination. METHODS: We tested serum IgG binding to SARS-CoV-2 spike protein and neutralising capacity in 110 healthcare workers, before and after both BNT162b2 messenger RNA (mRNA) vaccinations. We compared outcomes between participants with more recent infection (n = 18, median two months, IQR 2-3), with infection-vaccination interval over six months (n = 19, median nine months, IQR 9-10), and to those not previously infected (n = 73). FINDINGS: Both recently and earlier infected participants showed comparable humoral immune responses after a single mRNA vaccination, while exceeding those of previously uninfected persons after two vaccinations with 2.5 fold (p = 0.003) and 3.4 fold (p < 0.001) for binding antibody levels, and 6.4 and 7.2 fold for neutralisation titres, respectively (both p < 0.001). The second vaccine dose yielded no further substantial improvement of the humoral response in the previously infected participants (0.97 fold, p = 0.92), while it was associated with a 4 fold increase in antibody binding levels and 18 fold increase in neutralisation titres in previously uninfected participants (both p < 0.001). Adjustment for potential confounding of sex and age did not affect these findings. INTERPRETATION: Delaying the second vaccination in individuals infected up to ten months prior may constitute a more efficient use of limited vaccine supplies. FUNDING: Netherlands Organization for Health Research and Development ZonMw; Corona Research Fund Amsterdam UMC; Bill & Melinda Gates Foundation.


Subject(s)
Antibodies, Viral/blood , Antibody Formation , COVID-19 Vaccines/pharmacology , COVID-19 , SARS-CoV-2/immunology , Adult , COVID-19 Vaccines/therapeutic use , Female , Health Personnel , Humans , Immunity, Humoral , Immunoglobulin G/blood , Male , Middle Aged , Netherlands , Prospective Studies , Time Factors , Treatment Outcome
11.
Microbiol Spectr ; 9(2): e0073121, 2021 10 31.
Article in English | MEDLINE | ID: covidwho-1410324

ABSTRACT

COVID-19 patients produce circulating and mucosal antibodies. In adults, specific saliva antibodies have been detected. Nonetheless, seroprevalence is routinely investigated, while little attention has been paid to mucosal antibodies. We therefore assessed SARS-CoV-2-specific antibody prevalence in serum and saliva in children in the Netherlands. We assessed SARS-CoV-2 antibody prevalence in serum and saliva of 517 children attending medical services in the Netherlands (irrespective of COVID-19 exposure) from April to October 2020. The prevalence of SARS-CoV-2 spike (S), receptor binding domain (RBD), and nucleocapsid (N)-specific IgG and IgA were evaluated with an exploratory Luminex assay in serum and saliva and with the Wantai SARS-CoV-2 RBD total antibody enzyme-linked immunosorbent assay in serum. Using the Wantai assay, the RBD-specific antibody prevalence in serum was 3.3% (95% confidence interval [CI]. 1.9 to 5.3%). With the Luminex assay, we detected heterogeneity between antibodies for S, RBD, and N antigens, as IgG and IgA prevalence ranged between 3.6 and 4.6% in serum and between 0 and 4.4% in saliva. The Luminex assay also revealed differences between serum and saliva, with SARS-CoV-2-specific IgG present in saliva but not in serum for 1.5 to 2.7% of all children. Using multiple antigen assays, the IgG prevalence for at least two out of three antigens (S, RBD, or N) in serum or saliva can be calculated as 3.8% (95% CI, 2.3 to 5.6%). Our study displays the heterogeneity of the SARS-CoV-2 antibody response in children and emphasizes the additional value of saliva antibody detection and the combined use of different antigens. IMPORTANCE Comprehending humoral immunity to SARS-CoV-2, including in children, is crucial for future public health and vaccine strategies. Others have suggested that mucosal antibody measurement could be an important and more convenient tool to evaluate humoral immunity compared to circulating antibodies. Nonetheless, seroprevalence is routinely investigated, while little attention has been paid to mucosal antibodies. We show the heterogeneity of SARS-CoV-2 antibodies, in terms of both antigen specificity and differences between circulating and mucosal antibodies, emphasizing the additional value of saliva antibody detection next to detection of antibodies in serum.


Subject(s)
Antibodies, Viral/blood , COVID-19 Serological Testing/methods , Coronavirus Nucleocapsid Proteins/immunology , SARS-CoV-2/immunology , Saliva/immunology , Spike Glycoprotein, Coronavirus/immunology , Adolescent , COVID-19/diagnosis , Child , Child, Preschool , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunity, Humoral/immunology , Immunoglobulin A/blood , Immunoglobulin G/blood , Male , Phosphoproteins/immunology , Prevalence , Sensitivity and Specificity , Seroepidemiologic Studies
13.
Clin Infect Dis ; 2021 Sep 02.
Article in English | MEDLINE | ID: covidwho-1393222

ABSTRACT

BACKGROUND: Few robust longitudinal data on long-term COVID-19 symptoms are available. We evaluated symptom onset, severity and recovery across the full spectrum of disease severity, up to one year after illness onset. METHODS: The RECoVERED Study is a prospective cohort study based in Amsterdam, the Netherlands. Participants aged≥18 years were enrolled following SARS-CoV-2 diagnosis via the local Public Health Service and from hospitals. Standardised symptom questionnaires were completed at enrolment, one week and month later, and monthly thereafter. Clinical severity was defined according to WHO criteria. Kaplan-Meier methods were used to compare time from illness onset to symptom recovery, by clinical severity. We examined determinants of time to recovery using multivariable Cox proportional hazards models. RESULTS: Between 11 May 2020 and 1 May 2021, 342 COVID-19 patients (192[56%] male) were enrolled, of whom 99/342(29%) had mild, 145/342(42%) moderate, 56/342(16%) severe and 42/342(12%) critical disease. The proportion of participants who reported at least one persistent symptom at 12 weeks after illness onset was greater in those with severe/critical disease (86.7%[95%CI=76.5-92.7%]) compared to those with mild or moderate disease (30.7%[95%CI=21.1-40.9%] and 63.8%[95%CI=54.8-71.5%]). At twelve months after illness onset, two-fifths of participants (40.7%[95%CI=34.2-47.1]) continued to report ≥1 symptom. Recovery was slower in female compared to male participants (aHR 0.65[95%CI=0.47-0.92]) and those with a BMI≥30kg/m 2 compared to BMI<25kg/m 2 (HR 0.62[95%CI=0.39-0.97]). CONCLUSIONS: COVID-19 symptoms persisted for one year after illness onset, even in some individuals with mild disease. Female sex and obesity were the most important determinants of speed of recovery from symptoms.

14.
Nature ; 592(7853): 277-282, 2021 04.
Article in English | MEDLINE | ID: covidwho-1387425

ABSTRACT

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.


Subject(s)
COVID-19/drug therapy , COVID-19/therapy , COVID-19/virology , Evolution, Molecular , Mutagenesis/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Aged , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Chronic Disease , Genome, Viral/drug effects , Genome, Viral/genetics , High-Throughput Nucleotide Sequencing , Humans , Immune Evasion/drug effects , Immune Evasion/genetics , Immune Evasion/immunology , Immune Tolerance/drug effects , Immune Tolerance/immunology , Immunization, Passive , Male , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/immunology , Mutation , Phylogeny , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Time Factors , Viral Load/drug effects , Virus Shedding
15.
Sci Adv ; 7(22)2021 05.
Article in English | MEDLINE | ID: covidwho-1388434

ABSTRACT

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo-electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.


Subject(s)
COVID-19/immunology , Heme/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , Antibodies, Neutralizing/immunology , Bilirubin/metabolism , Biliverdine/metabolism , Cryoelectron Microscopy , Crystallography, X-Ray , Epitopes , Humans , Immune Sera , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity
16.
Cell Rep ; 33(3): 108274, 2020 10 20.
Article in English | MEDLINE | ID: covidwho-1385223

ABSTRACT

IGHV3-53-encoded neutralizing antibodies are commonly elicited during SARS-CoV-2 infection and target the receptor-binding domain (RBD) of the spike (S) protein. Such IGHV3-53 antibodies generally have a short CDR H3 because of structural constraints in binding the RBD (mode A). However, a small subset of IGHV3-53 antibodies to the RBD contain a longer CDR H3. Crystal structures of two IGHV3-53 neutralizing antibodies here demonstrate that a longer CDR H3 can be accommodated in a different binding mode (mode B). These two classes of IGHV3-53 antibodies both target the ACE2 receptor binding site, but with very different angles of approach and molecular interactions. Overall, these findings emphasize the versatility of IGHV3-53 in this common antibody response to SARS-CoV-2, where conserved IGHV3-53 germline-encoded features can be combined with very different CDR H3 lengths and light chains for SARS-CoV-2 RBD recognition and virus neutralization.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Betacoronavirus/immunology , Spike Glycoprotein, Coronavirus/immunology , COVID-19 , Complementarity Determining Regions/immunology , Coronavirus Infections/virology , Crystallography, X-Ray , Humans , Immunoglobulin Heavy Chains/immunology , Neutralization Tests , Pandemics , Pneumonia, Viral/virology , Protein Domains/immunology , SARS-CoV-2
17.
J Hum Lact ; 37(3): 485-491, 2021 08.
Article in English | MEDLINE | ID: covidwho-1325271

ABSTRACT

BACKGROUND: Human milk contains antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) following Coronavirus Disease 2019 (COVID-19). These antibodies may serve as protection against COVID-19 in infants. However, the evolution of these human milk antibodies over time is unclear. RESEARCH AIM: To elucidate the evolution of immunoglobulin A (IgA) against SARS-CoV-2 in human milk after a SARS-CoV-2 infection. METHODS: This longitudinal follow-up study included lactating mothers (N = 24) who had participated in the COVID MILK study. To assess the evolution of SARS-CoV-2 antibodies, serum and human milk samples were collected 14-143 days after the onset of clinical symptoms related to COVID-19. Enzyme-Linked ImmunoSorbent Assay was used to detect antibodies against the ectodomain of the SARS-CoV-2 spike protein. RESULTS: SARS-CoV-2 antibodies remain present up to 5 months (143 days) in human milk after onset of COVID-19 symptoms. Overall, SARS-CoV-2 IgA in human milk seems to gradually decrease over time. CONCLUSION: Human milk from SARS-CoV-2 convalescent lactating mothers contains specific IgA antibodies against SARS-CoV-2 spike protein up to at least 5 months post-infection. Passive viral immunity can be transferred via human milk and may serve as protection for infants against COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Breast Feeding , Female , Follow-Up Studies , Humans , Infant , Lactation , Milk, Human , Spike Glycoprotein, Coronavirus
18.
J Hum Lact ; 37(3): 477-484, 2021 08.
Article in English | MEDLINE | ID: covidwho-1285158

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are being administered around the world; however, lactating women were excluded from SARS-CoV-2 vaccine trials. Therefore, knowledge about the effect of vaccination in this specific group is limited. This information is essential to empower lactating women to make a well-informed decision on their choice for vaccination. After natural infection, SARS-CoV-2 specific antibodies are present in human milk, which might offer protection for her newborn. The dynamics of these antibodies in human milk following vaccination remain to be elucidated. RESEARCH AIM: To determine the effect of vaccination with BNT162b2 on the levels of SARS-CoV-2 specific IgA in human milk. METHODS: In this prospective longitudinal study, we included lactating women who received the BNT162b2 vaccine. Human milk samples were collected prior to vaccination and 3, 5, 7, 9, 11, 13, and 15 days after both vaccine doses. Samples were analyzed using enzyme-linked immunosorbent assay against the spike protein of SARS-CoV-2. RESULTS: In total, 366 human milk samples from 26 lactating women were analyzed. A biphasic response was observed, with SARS-CoV-2 specific immunoglobulin A (IgA) starting to increase between day 5 and 7 after the first dose of the vaccine. After the second dose, an accelerated IgA antibody response was observed. CONCLUSION: After vaccination with the mRNA-based BNT162b2 vaccine, a SARS-CoV-2 specific antibody response was observed in human milk. The presence of SARS-CoV-2 specific IgA after vaccination is important as antibodies are transferred via human milk, and thereby might provide protection to infants against COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Breast Feeding , COVID-19 Vaccines , Female , Humans , Infant, Newborn , Lactation , Longitudinal Studies , Milk, Human , Prospective Studies , Vaccination
19.
Sci Immunol ; 6(59)2021 05 25.
Article in English | MEDLINE | ID: covidwho-1243688

ABSTRACT

The emergence of SARS-CoV-2 variants harboring mutations in the spike (S) protein has raised concern about potential immune escape. Here, we studied humoral and cellular immune responses to wild type SARS-CoV-2 and the B.1.1.7 and B.1.351 variants of concern in a cohort of 121 BNT162b2 mRNA-vaccinated health care workers (HCW). Twenty-three HCW recovered from mild COVID-19 disease and exhibited a recall response with high levels of SARS-CoV-2-specific functional antibodies and virus-specific T cells after a single vaccination. Specific immune responses were also detected in seronegative HCW after one vaccination, but a second dose was required to reach high levels of functional antibodies and cellular immune responses in all individuals. Vaccination-induced antibodies cross-neutralized the variants B.1.1.7 and B.1.351, but the neutralizing capacity and Fc-mediated functionality against B.1.351 was consistently 2- to 4-fold lower than to the homologous virus. In addition, peripheral blood mononuclear cells were stimulated with peptide pools spanning the mutated S regions of B.1.1.7 and B.1.351 to detect cross-reactivity of SARS-CoV-2-specific T cells with variants. Importantly, we observed no differences in CD4+ T-cell activation in response to variant antigens, indicating that the B.1.1.7 and B.1.351 S proteins do not escape T-cell-mediated immunity elicited by the wild type S protein. In conclusion, this study shows that some variants can partially escape humoral immunity induced by SARS-CoV-2 infection or BNT162b2 vaccination, but S-specific CD4+ T-cell activation is not affected by the mutations in the B.1.1.7 and B.1.351 variants.


Subject(s)
Antibodies, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , COVID-19 Vaccines/immunology , Cell Line , Cross Reactions/immunology , Humans , Immunologic Memory/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccination
20.
Science ; 373(6556): 818-823, 2021 08 13.
Article in English | MEDLINE | ID: covidwho-1238481

ABSTRACT

Neutralizing antibodies (nAbs) elicited against the receptor binding site (RBS) of the spike protein of wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are generally less effective against recent variants of concern. RBS residues Glu484, Lys417, and Asn501 are mutated in variants first described in South Africa (B.1.351) and Brazil (P.1). We analyzed their effects on angiotensin-converting enzyme 2 binding, as well as the effects of two of these mutations (K417N and E484K) on nAbs isolated from COVID-19 patients. Binding and neutralization of the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2), which can both bind the RBS in alternative binding modes, are abrogated by K417N, E484K, or both. These effects can be structurally explained by their extensive interactions with RBS nAbs. However, nAbs to the more conserved, cross-neutralizing CR3022 and S309 sites were largely unaffected. The results have implications for next-generation vaccines and antibody therapies.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antigens, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Antigenic Variation , Antigens, Viral/chemistry , Antigens, Viral/genetics , Antigens, Viral/metabolism , Binding Sites , Binding Sites, Antibody , COVID-19/virology , Epitopes , Humans , Immune Evasion , Mutation , Protein Binding , Protein Domains , Receptors, Coronavirus/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...