José-María Díez

Bio: José-María Díez is an academic researcher. The author has contributed to research in topics: Neutralization & Population. The author has an hindex of 3, co-authored 4 publications receiving 72 citations.

Currently available intravenous immunoglobulin contains antibodies reacting against severe acute respiratory syndrome coronavirus 2 antigens.

Abstract: Aim: There is a critical need for effective therapies that are immediately available to control the spread of COVID-19 disease. Material & methods: Gamunex®-C and Flebogamma® DIF (Grifols) intravenous immunoglobulin (IVIG) products were tested using ELISA techniques for antibodies against several antigens of human common betacoronaviruses that may crossreact with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Results: Both IVIGs showed consistent reactivity to components of the tested viruses. Positive crossreactivity was seen in SARS-CoV, middle east respiratory syndrome-CoV and SARS-CoV-2. For SARS-CoV-2, positive reactivity was observed at IVIG concentrations ranging from 100 μg/ml with Gamunex-C to 1 mg/ml with Flebogamma 5% DIF. Conclusion: Gamunex-C and Flebogamma DIF contain antibodies reacting against SARS-CoV-2 antigens. Studies to confirm the utility of IVIG preparations for COVID-19 management may be warranted.

Currently available intravenous immunoglobulin (Gamunex(C)-C and Flebogamma(C) DIF) contains antibodies reacting against SARS-CoV-2 antigens

Abstract: Background There is a critical need for effective therapies that are immediately available to control the spread of COVID-19 disease. In this study, we assessed currently marketed intravenous immunoglobulin (IVIG) products for antibodies against human common coronaviruses that may cross-react with the SARS-CoV-2 virus. Methods Gamunex®-C and Flebogamma® DIF (Grifols) IVIG were tested against several betacoronaviruses antigens using ELISA techniques: HCoV (undetermined antigen), HCoV-HKU1 (N protein), SARS-CoV (culture lysate), MERS-CoV (N protein; S1 protein/RBD; S protein), and SARS-CoV-2 (S1 protein). Results Both IVIG products showed consistent reactivity to components of the tested viruses. Positive cross-reactivity was seen in SARS-CoV, MERS-CoV, and SARS-CoV-2. For SARS-CoV-2, positive reactivity was observed at IVIG concentrations ranging from 100 μg/mL with Gamunex-C to 1 mg/mL with Flebogamma 5% DIF. Conclusion Gamunex-C and Flebogamma DIF IVIG contain antibodies reacting against SARS-CoV-2 antigens. These preparations may be useful for immediate treatment of COVID-19 disease.

Effective presence of antibodies against common human coronavirus in IgG immunoglobulin medicinal products.

Abstract: Introduction In this series of studies, immunoglobulin products (IgG) formulated for different routes of administration (IV, IM, SC) and prepared from geographically diverse plasma pools were tested for activity against common human coronaviruses (HCoV). IgG products from plasma obtained from Germany, Czech Republic, Slovak Republic, USA and Spain were tested for antibodies to four common HCoV: 229E, OC43, NL63 and HKU1. Since these products are manufactured from pooled plasma from thousands of donors, the antibodies therein are a representation of the HCoV exposure of the population at large. Methods IgG products of different concentrations manufactured from geographically diverse plasma pools were tested for antibodies to four common HCoV by ELISA. In addition, neutralization assays were conducted using HCoV-229E expressed in MRC5 cells. Complete concentration-neutralization curves were obtained to calculate potencies. Results The ELISA assays showed that when expressed as specific activity (anti-HCoV activity/mg IgG) similar activity against the four common HCoV was seen across the IgG products regardless of concentration or geographic origin. Highest anti-HCoV activity was seen against HCoV-229E, followed by HCoV-OC43 and then HCoV-NL63 and HCoV-HKU1. The neutralization assays showed similar potency for two preparations of IgG prepared by different processes. Conclusions These studies are the first demonstration of antibodies to common HCoV in IgG products. The level of activity was similar regardless of the geographic origin of the plasma pool. These antibodies demonstrated neutralization activity against HCoV-229E in MRC5 cells. These results may explain the cross-reactivity seen with pre-pandemic IgG products and SARS-CoV-2 and contribute to the variability in disease course in different patients.

Anti-SARS-CoV-2 hyperimmune immunoglobulin provides potent and robust neutralization capacity and antibody-dependent cellular cytotoxicity and phagocytosis induction through N and S proteins

Abstract: Background Although progressive COVID-19 vaccinations provide a significant reduction of infection rate in the short-to mid-term, effective COVID-19 treatments will continue to be an urgent need. Methods We have functionally characterized the anti-SARS-CoV-2 hyperimmune immunoglobulin (hIG) prepared from human COVID-19 convalescent plasma. SARS-CoV-2 virus neutralization was evaluated by four different methodologies (plaque reduction, virus induced cytotoxicity, TCID50 reduction and immunofluorimetry-based methodology) performed at four different laboratories and using four geographically different SARS-CoV-2 isolates (one each from USA and Italy; two from Spain). Two of the isolates contained the D614G mutation. Neutralization capacity against the original Wuhan SARS-CoV-2 straom and variants (D614G mutant, B.1.1.7, P.1 and B.1.351 variants) was evaluated using a pseudovirus platform expressing the corresponding spike (S) protein. The capacity to induce antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) was also evaluated. Results All the SARS-CoV-2 isolates tested were effectively neutralized by hIG solutions. This was confirmed by all four methodologies showing potent neutralization capacity. Wild-type SARS-CoV-2 and variants were effectively neutralized as demonstrated using the pseudovirus platform. The hIG solutions had the capacity to induce ADCC and ADCP against SARS-CoV-2 N and S proteins but not the E protein. Under our experimental conditions, very low concentrations (25-100 µg IgG/mL) were required to induce both effects. Besides the S protein, we observed a clear and potent effect triggered by antibodies in the hIG solutions against the SARS-CoV-2 N protein. Conclusions These results show that, beyond neutralization, other IgG Fc-dependent pathways may play a role in the protection from and/or resolution of SARS-CoV-2 infection when using hIG COVID-19 products. This could be especially relevant for the treatment of more neutralization resistant SARS-CoV-2 variants of concern.

Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review.

Abstract: Background Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are currently being investigated in trials as potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required. OBJECTIVES: To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in treatment of people with COVID-19. Search methods We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trial registries to identify completed and ongoing studies on 4 June 2020. Selection criteria We followed standard Cochrane methodology. We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of study design, disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulin. Data collection and analysis We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of bias' tool for randomised controlled trials (RCTs), the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool for controlled non-randomised studies of interventions (NRSIs), and the assessment criteria for observational studies, provided by Cochrane Childhood Cancer for non-controlled NRSIs. MAIN RESULTS: This is the first living update of our review. We included 20 studies (1 RCT, 3 controlled NRSIs, 16 non-controlled NRSIs) with 5443 participants, of whom 5211 received convalescent plasma, and identified a further 98 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, of which 50 are randomised. We did not identify any completed studies evaluating hyperimmune immunoglobulin. Overall risk of bias of included studies was high, due to study design, type of participants, and other previous or concurrent treatments. Effectiveness of convalescent plasma for people with COVID-19 We included results from four controlled studies (1 RCT (stopped early) with 103 participants, of whom 52 received convalescent plasma; and 3 controlled NRSIs with 236 participants, of whom 55 received convalescent plasma) to assess effectiveness of convalescent plasma. Control groups received standard care at time of treatment without convalescent plasma. All-cause mortality at hospital discharge (1 controlled NRSI, 21 participants) We are very uncertain whether convalescent plasma has any effect on all-cause mortality at hospital discharge (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.61 to 1.31; very low-certainty evidence). Time to death (1 RCT, 103 participants; 1 controlled NRSI, 195 participants) We are very uncertain whether convalescent plasma prolongs time to death (RCT: hazard ratio (HR) 0.74, 95% CI 0.30 to 1.82; controlled NRSI: HR 0.46, 95% CI 0.22 to 0.96; very low-certainty evidence). Improvement of clinical symptoms, assessed by need for respiratory support (1 RCT, 103 participants; 1 controlled NRSI, 195 participants) We are very uncertain whether convalescent plasma has any effect on improvement of clinical symptoms at seven days (RCT: RR 0.98, 95% CI 0.30 to 3.19), 14 days (RCT: RR 1.85, 95% CI 0.91 to 3.77; controlled NRSI: RR 1.08, 95% CI 0.91 to 1.29), and 28 days (RCT: RR 1.20, 95% CI 0.80 to 1.81; very low-certainty evidence). Quality of life No studies reported this outcome. Safety of convalescent plasma for people with COVID-19 We included results from 1 RCT, 3 controlled NRSIs and 10 non-controlled NRSIs assessing safety of convalescent plasma. Reporting of adverse events and serious adverse events was variable. The controlled studies reported on adverse events and serious adverse events only in participants receiving convalescent plasma. The duration of follow-up varied. Some, but not all, studies included death as a serious adverse event. Grade 3 or 4 adverse events (13 studies, 201 participants) The studies did not report the grade of adverse events. Thirteen studies (201 participants) reported on adverse events of possible grade 3 or 4 severity. The majority of these adverse events were allergic or respiratory events. We are very uncertain whether or not convalescent plasma therapy affects the risk of moderate to severe adverse events (very low-certainty evidence). Serious adverse events (14 studies, 5201 participants) Fourteen studies (5201 participants) reported on serious adverse events. The majority of participants were from one non-controlled NRSI (5000 participants), which reported only on serious adverse events limited to the first four hours after convalescent plasma transfusion. This study included death as a serious adverse event; they reported 15 deaths, four of which they classified as potentially, probably or definitely related to transfusion. Other serious adverse events reported in all studies were predominantly allergic or respiratory in nature, including anaphylaxis, transfusion-associated dyspnoea, and transfusion-related acute lung injury (TRALI). We are very uncertain whether or not convalescent plasma affects the number of serious adverse events. Authors' conclusions We are very uncertain whether convalescent plasma is beneficial for people admitted to hospital with COVID-19. For safety outcomes we also included non-controlled NRSIs. There was limited information regarding adverse events. Of the controlled studies, none reported on this outcome in the control group. There is only very low-certainty evidence for safety of convalescent plasma for COVID-19. While major efforts to conduct research on COVID-19 are being made, problems with recruiting the anticipated number of participants into these studies are conceivable. The early termination of the first RCT investigating convalescent plasma, and the multitude of studies registered in the past months illustrate this. It is therefore necessary to critically assess the design of these registered studies, and well-designed studies should be prioritised. Other considerations for these studies are the need to report outcomes for all study arms in the same way, and the importance of maintaining comparability in terms of co-interventions administered in all study arms. There are 98 ongoing studies evaluating convalescent plasma and hyperimmune immunoglobulin, of which 50 are RCTs. This is the first living update of the review, and we will continue to update this review periodically. These updates may show different results to those reported here.

Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review.

Abstract: BACKGROUND: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with respiratory virus diseases, and are currently being investigated in trials as a potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required. OBJECTIVES: To assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID-19. SEARCH METHODS: The protocol was pre-published with the Center for Open Science and can be accessed here: osf.io/dwf53 We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trials registries to identify ongoing studies and results of completed studies on 23 April 2020 for case-series, cohort, prospectively planned, and randomised controlled trials (RCTs). SELECTION CRITERIA: We followed standard Cochrane methodology and performed all steps regarding study selection in duplicate by two independent review authors (in contrast to the recommendations of the Cochrane Rapid Reviews Methods Group). We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulins. DATA COLLECTION AND ANALYSIS: We followed recommendations of the Cochrane Rapid Reviews Methods Group regarding data extraction and assessment. To assess bias in included studies, we used the assessment criteria tool for observational studies, provided by Cochrane Childhood Cancer. We rated the certainty of evidence using the GRADE approach for the following outcomes: all-cause mortality at hospital discharge, improvement of clinical symptoms (7, 15, and 30 days after transfusion), grade 3 and 4 adverse events, and serious adverse events. MAIN RESULTS: We included eight studies (seven case-series, one prospectively planned, single-arm intervention study) with 32 participants, and identified a further 48 ongoing studies evaluating convalescent plasma (47 studies) or hyperimmune immunoglobulin (one study), of which 22 are randomised. Overall risk of bias of the eight included studies was high, due to: study design; small number of participants; poor reporting within studies; and varied type of participants with different severities of disease, comorbidities, and types of previous or concurrent treatments, including antivirals, antifungals or antibiotics, corticosteroids, hydroxychloroquine and respiratory support. We rated all outcomes as very low certainty, and we were unable to summarise numerical data in any meaningful way. As we identified case-series studies only, we reported results narratively. Effectiveness of convalescent plasma for people with COVID-19 The following reported outcomes could all be related to the underlying natural history of the disease or other concomitant treatment, rather than convalescent plasma. All-cause mortality at hospital discharge All studies reported mortality. All participants were alive at the end of the reporting period, but not all participants had been discharged from hospital by the end of the study (15 participants discharged, 6 still hospitalised, 11 unclear). Follow-up ranged from 3 days to 37 days post-transfusion. We do not know whether convalescent plasma therapy affects mortality (very low-certainty evidence). Improvement of clinical symptoms (assessed by respiratory support) Six studies, including 28 participants, reported the level of respiratory support required; most participants required respiratory support at baseline. All studies reported improvement in clinical symptoms in at least some participants. We do not know whether convalescent plasma improves clinical symptoms (very low-certainty evidence). Time to discharge from hospital Six studies reported time to discharge from hospital for at least some participants, which ranged from four to 35 days after convalescent plasma therapy. Admission on the intensive care unit (ICU) Six studies included patients who were critically ill. At final follow-up the majority of these patients were no longer on the ICU or no longer required mechanical ventilation. Length of stay on the ICU Only one study (1 participant) reported length of stay on the ICU. The individual was discharged from the ICU 11 days after plasma transfusion. Safety of convalescent plasma for people with COVID-19 Grade 3 or 4 adverse events The studies did not report the grade of adverse events after convalescent plasma transfusion. Two studies reported data relating to participants who had experienced adverse events, that were presumably grade 3 or 4. One case study reported a participant who had moderate fever (38.9 °C). Another study (3 participants) reported a case of severe anaphylactic shock. Four studies reported the absence of moderate or severe adverse events (19 participants). We are very uncertain whether or not convalescent plasma therapy affects the risk of moderate to severe adverse events (very low-certainty evidence). Serious adverse events One study (3 participants) reported one serious adverse event. As described above, this individual had severe anaphylactic shock after receiving convalescent plasma. Six studies reported that no serious adverse events occurred. We are very uncertain whether or not convalescent plasma therapy affects the risk of serious adverse events (very low-certainty evidence). AUTHORS' CONCLUSIONS: We identified eight studies (seven case-series and one prospectively planned single-arm intervention study) with a total of 32 participants (range 1 to 10). Most studies assessed the risks of the intervention; reporting two adverse events (potentially grade 3 or 4), one of which was a serious adverse event. We are very uncertain whether convalescent plasma is effective for people admitted to hospital with COVID-19 as studies reported results inconsistently, making it difficult to compare results and to draw conclusions. We identified very low-certainty evidence on the effectiveness and safety of convalescent plasma therapy for people with COVID-19; all studies were at high risk of bias and reporting quality was low. No RCTs or controlled non-randomised studies evaluating benefits and harms of convalescent plasma have been completed. There are 47 ongoing studies evaluating convalescent plasma, of which 22 are RCTs, and one trial evaluating hyperimmune immunoglobulin. We will update this review as a living systematic review, based on monthly searches in the above mentioned databases and registries. These updates are likely to show different results to those reported here.

Convalescent Plasma Therapy for COVID-19: State of the Art.

Abstract: Convalescent plasma (CP) therapy has been used since the early 1900s to treat emerging infectious diseases; its efficacy was later associated with the evidence that polyclonal neutralizing antibodies can reduce the duration of viremia. Recent large outbreaks of viral diseases for which effective antivirals or vaccines are still lacking has renewed the interest in CP as a life-saving treatment. The ongoing COVID-19 pandemic has led to the scaling up of CP therapy to unprecedented levels. Compared with historical usage, pathogen reduction technologies have now added an extra layer of safety to the use of CP, and new manufacturing approaches are being explored. This review summarizes historical settings of application, with a focus on betacoronaviruses, and surveys current approaches for donor selection and CP collection, pooling technologies, pathogen inactivation systems, and banking of CP. We additionally list the ongoing registered clinical trials for CP throughout the world and discuss the trial results published thus far.

Antibody-based immunotherapeutics and use of convalescent plasma to counter COVID-19: advances and prospects.

Abstract: Coronavirus disease 2019 (COVID-19) has spread to several countries globally. Currently, there is no specific drug or vaccine available for managing COVID-19. Antibody-based immunotherapeutic strat...