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medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.11.30.21266810


Background: Convalescent plasma (CP) for hospitalized patients with COVID-19 has not demonstrated clear benefits. However, data on outpatients with early symptoms are scarce. We aimed to assess whether treatment with CP administered during the first 7 days of symptoms reduced the disease progression or risk of hospitalization of outpatients. Methods: Two double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when <20% of their predefined sample size had been recruited. A Bayesian adaptive individual patient data meta-analysis was implemented. Analyses were done with Bayesian proportional odds and logistic models, where odds ratios (OR)<1.0 indicate a favorable outcome for CP. Fourteen study sites across the Netherlands and Catalonia in Spain participated in the trial. The two studies included outpatients aged [≥]50 years and diagnosed with COVID-19 and symptomatic for [≤]7days. The intervention consisted of one unit (200-300mL) of CP with a predefined minimum level of antibodies. The two primary endpoints were (a) a 5-point disease severity scale (fully recovered by day 7 or not, hospital or ICU admission and death) and (b) a composite of hospitalization or death. Results: Of 797 patients included, 390 received CP and 392 placebo. At baseline, they had a median age of 58 years, 1 comorbidity, symptoms for 5 days and 93% tested negative for SARS-CoV-2 S-protein IgG antibodies. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The OR of CP for an improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311). The OR for hospitalization or death was 0.919 (CI 0.592-1.416). The effect of CP on hospital admission or death was largest in patients with [≤]5 days of symptoms (OR 0.658, 95% CI 0.394-1.085). CP did not decrease the time to full symptom resolution (p=0.62). Conclusion: Treatment with CP of outpatients in the first 7 days of symptoms did not improve the outcome of COVID-19. The possible beneficial effect in patients with [≤]5 days of symptoms requires further study. Registration: NCT04621123 and NCT04589949 on

Science ; 371(6532)2021 02 26.
Article in English | MEDLINE | ID: covidwho-1066801


Immunoglobulin G (IgG) antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc tail, which is essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anticancer therapeutic antibodies for their increased activity through Fc receptors (FcγRIIIa). Here, we report that afucosylated IgG (approximately 6% of total IgG in humans) are specifically formed against enveloped viruses but generally not against other antigens. This mediates stronger FcγRIIIa responses but also amplifies brewing cytokine storms and immune-mediated pathologies. Critically ill COVID-19 patients, but not those with mild symptoms, had high concentrations of afucosylated IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), amplifying proinflammatory cytokine release and acute phase responses. Thus, antibody glycosylation plays a critical role in immune responses to enveloped viruses, including COVID-19.

Antibodies, Viral/immunology , COVID-19/immunology , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Viral/blood , Antibodies, Viral/chemistry , COVID-19/physiopathology , Cells, Cultured , Critical Illness , Cytomegalovirus/immunology , Female , Fucose/analysis , Glycosylation , HIV/immunology , Hepatitis B Vaccines/immunology , Humans , Immunoglobulin Fc Fragments/chemistry , Immunoglobulin Fc Fragments/immunology , Immunoglobulin G/blood , Immunoglobulin G/chemistry , Inflammation , Interleukin-6/biosynthesis , Interleukin-6/immunology , Macrophages/immunology , Male , Middle Aged , Parvovirus B19, Human/immunology , Severity of Illness Index , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Subunit/immunology , Young Adult
medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.06.17.20133793


SARS-CoV-2 infections often cause only mild disease that may evoke relatively low antibody titers compared to patients admitted to hospitals. Generally, total antibody bridging assays combine good sensitivity with high selectivity. Therefore, we developed sensitive total antibody bridging assays for detection of SARS-CoV-2 antibodies to the receptor-binding domain (RBD) and nucleocapsid protein (NP), in addition to conventional isotype-specific assays. Antibody kinetics was assessed in PCR-confirmed hospitalized COVID-19 patients (n=41) and three populations of patients with COVID-19 symptoms not requiring hospital admission: PCR-confirmed convalescent plasmapheresis donors (n=182), PCR-confirmed hospital care workers (n=47), and a group of longitudinally sampled symptomatic individuals highly suspect of COVID-19 (n=14). In non-hospitalized patients, the antibody response to RBD is weaker but follows similar kinetics as has been observed in hospitalized patients. Across populations, the RBD bridging assay identified most patients correctly as seropositive. In 11/14 of the COVID-19-suspect cases, seroconversion in the RBD bridging assay could be demonstrated before day 12; NP antibodies emerged less consistently. Furthermore, we demonstrated the feasibility of finger prick sampling for antibody detection against SARS-CoV-2 using these assays. In conclusion, the developed bridging assays reliably detect SARS-CoV-2 antibodies in hospitalized and non-hospitalized patients, and are therefore well-suited to conduct seroprevalence studies.

biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.06.18.159202


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. Understanding both the immunological processes providing specific immunity and potential immunopathology underlying the pathogenesis of this disease may provide valuable insights for potential therapeutic interventions. Here, we quantified SARS-CoV-2 specific immune responses in patients with different clinical courses. Compared to individuals with a mild clinical presentation, CD4+ T cell responses were qualitatively impaired in critically ill patients. Strikingly, however, in these patients the specific IgG antibody response was remarkably strong. The observed disparate T and B cell responses could be indicative of a deregulated immune response in critically ill COVID-19 patients.

biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.05.18.099507


IgG antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc-tail, essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anti-cancer therapeutic antibodies for their elevated binding and killing activity through Fc receptors (Fc{gamma}RIIIa). Here, we report that afucosylated IgG which are of minor abundance in humans ([~]6% of total IgG) are specifically formed against surface epitopes of enveloped viruses after natural infections or immunization with attenuated viruses, while protein subunit immunization does not elicit this low fucose response. This can give beneficial strong responses, but can also go awry, resulting in a cytokine-storm and immune-mediated pathologies. In the case of COVID-19, the critically ill show aggravated afucosylated-IgG responses against the viral spike protein. In contrast, those clearing the infection unaided show higher fucosylation levels of the anti-spike protein IgG. Our findings indicate antibody glycosylation as a potential factor in inflammation and protection in enveloped virus infections including COVID-19.