Hyperimmune Immunoglobulin Research Articles

Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial

BackgroundPassive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited.MethodsIn this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581.FindingsFrom Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001).InterpretationWhen administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry.FundingUS National Institutes of Health.

Anti-Severe Acute Respiratory Syndrome Coronavirus 2 Hyperimmune Immunoglobulin Demonstrates Potent Neutralization and Antibody-Dependent Cellular Cytotoxicity and Phagocytosis Through N and S Proteins.

BackgroundAlthough coronavirus disease 2019 (COVID-19) vaccinations have provided a significant reduction in infections, effective COVID-19 treatments remain an urgent need.MethodsFunctional characterization of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hyperimmune immunoglobulin (hIG) from human convalescent plasma was performed by different virus neutralization methodologies (plaque reduction, virus-induced cytotoxicity, median tissue culture infectious dose [TCID50] reduction, and immunofluorimetry) at different laboratories using geographically different SARS-CoV-2 isolates (USA [1], Italy [1], and Spain [2]; 2 containing the D614G mutation). Neutralization capacity against the original Wuhan SARS-CoV-2 strain and variants (D614G mutant, B.1.1.7, P.1, and B.1.351) was evaluated using a pseudovirus expressing the corresponding spike (S) protein. Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) was also evaluated.ResultsAll SARS-CoV-2 isolates were potently neutralized by hIG as shown by all 4 methodologies. Wild-type SARS-CoV-2 and variants were effectively neutralized using the pseudovirus. The hIG (IgG type) induced ADCC and ADCP against SARS-CoV-2 N and S proteins but not E protein. Very low concentrations (25–100 µg IgG/mL) were required. A potent effect was triggered by antibodies in hIG solutions against the SARS-CoV-2 S and N proteins.ConclusionsBeyond neutralization, IgG Fc-dependent pathways may play a role in combatting SARS-CoV-2 infections using COVID-19 hIG. This could be especially relevant for the treatment of more neutralization-resistant SARS-CoV-2 variants.

Hyperimmune immunoglobulin for people with COVID-19

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: Using a living systematic review approach, to assess whether hyperimmune immunoglobulin therapy is effective and safe in the treatment of people with COVID‐19; and to maintain the currency of the evidence.

Antibody therapy for COVID-19.

Purpose of reviewTo provide an update of the current state of antibody therapy for Severe Acute Respiratory Syndrome Coronavirus 2 infection that has progressed immensely in a very short time period.Recent findingsLimited clinical effect of classical passive immunotherapy (plasma therapy, hyperimmune immunoglobulin [IgG] preparations) whereas monoclonal antibody therapy, if initiated early in the disease process, shows promising results.SummaryAlthough antibody therapy still remains to be fully explored in patients with COVID-19, a combination of IgG monoclonal antibodies against the receptor-binding domain of the spike protein currently appears to provide the best form of antibody therapy, Immunoglobulin A dimers and Immunoglobulin M pentamers also show promising preliminary therapeutic results.

Hyper-Enriched Anti-RSV Immunoglobulins Nasally Administered: A Promising Approach for Respiratory Syncytial Virus Prophylaxis.

Respiratory syncytial virus (RSV) is a public health concern that causes acute lower respiratory tract infection. So far, no vaccine candidate under development has reached the market and the only licensed product to prevent RSV infection in at-risk infants and young children is a monoclonal antibody (Synagis®). Polyclonal human anti-RSV hyper-immune immunoglobulins (Igs) have also been used but were superseded by Synagis® owing to their low titer and large infused volume. Here we report a new drug class of immunoglobulins, derived from human non hyper-immune plasma that was generated by an innovative bioprocess, called Ig cracking, combining expertises in plasma-derived products and affinity chromatography. By using the RSV fusion protein (F protein) as ligand, the Ig cracking process provided a purified and concentrated product, designated hyper-enriched anti-RSV IgG, composed of at least 15-20% target-specific-antibodies from normal plasma. These anti-RSV Ig displayed a strong in vitro neutralization effect on RSV replication. Moreover, we described a novel prophylactic strategy based on local nasal administration of this unique hyper-enriched anti-RSV IgG solution using a mouse model of infection with bioluminescent RSV. Our results demonstrated that very low doses of hyper-enriched anti-RSV IgG can be administered locally to ensure rapid and efficient inhibition of virus infection. Thus, the general hyper-enriched Ig concept appeared a promising approach and might provide solutions to prevent and treat other infectious diseases.ImportanceRespiratory Syncytial Virus (RSV) is the major cause of acute lower respiratory infections in children, and is also recognized as a cause of morbidity in the elderly. There are still no vaccines and no efficient antiviral therapy against this virus. Here, we described an approach of passive immunization with a new class of hyper-enriched anti-RSV immunoglobulins (Ig) manufactured from human normal plasma. This new class of immunoglobulin plasma derived product is generated by an innovative bioprocess, called Ig cracking, which requires a combination of expertise in both plasma derived products and affinity chromatography. The strong efficacy in a small volume of these hyper-enriched anti-RSV IgG to inhibit the viral infection was demonstrated using a mouse model. This new class of immunoglobulin plasma-derived products could be applied to other pathogens to address specific therapeutic needs in the field of infectious diseases or even pandemics, such as COVID-19.

Epitope Diversity and SARS-CoV-2 Variants Neutralizing Capacity of SARS-CoV-2 Hyperimmune Intravenous Immunoglobulins for Treatment of COVID-19

Hyperimmune immunoglobulin (hCoV-2IG) preparations generated from SARS-CoV-2 convalescent plasma (CP) are under evaluation in several clinical trials of hospitalized COVID-19 patients. Here we explored the antibody epitope repertoire, antibody binding and virus neutralizing capacity of six hCoV-2IG batches as well as nine convalescent plasma (CP) lots against SARS-CoV-2 and emerging variants of concern (VOC). The Gene-Fragment Phage display library spanning the SARS-CoV-2 spike-based epitope-mapping demonstrated broad recognition of multiple antigenic sites spanning the entire spike including NTD, RBD, S1/S2 cleavage site, S2-fusion peptide and S2-heptad repeat regions. Antibody binding to the immunodominant epitopes was higher for hCoV-2IG than CP, with predominant binding to the fusion peptide. In the pseudovirus neutralization assay (PsVNA) and in the wild-type SARS-CoV-2 PRNT assay, hCoV-2IG lots showed higher titers against the WA-1 strain compared with CP. Neutralization of SARS-CoV-2 VOCs from around the globe were reduced to a different extent by hCoV-2IG lots. The most significant loss of neutralizing activity was seen against the B.1.351 (9-fold) followed by P.1 (3.5-fold), with minimal loss of activity against the B.1.17 and B.1.429 ( Funding: The research work described in this manuscript was supported by FDA Medical Countermeasures Initiative (MCMi) grant # OCET 2021-1565 and NIH-NIAID IAA #AAI20040. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Declaration of Interest: The authors declare no competing interests.Ethical Approval: This study was approved by Food and Drug Administration’s Research Involving Human Subjects Committee (RIHSC #2020-04-02). This study complied with all relevant ethical regulations for work with human participants, and informed consent was obtained. Samples were collected from patients who provided informed consent to participate in the study.

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

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

Convalescent plasma in patients hospitalised with COVID-19

Convalescent plasma in patients hospitalised with COVID-19

Convalescent plasma and hyperimmune immunoglobulin to prevent infection with SARS-CoV-2

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe to prevent infection with SARS‐CoV‐2 and development of COVID‐19; and to maintain the currency of the evidence, using a living systematic review approach.

A Retrospective Study on the Effects of Convalescent Plasma Therapy in 24 Patients Diagnosed with COVID-19 Pneumonia in February and March 2020 at 2 Centers in Wuhan, China.

BackgroundThis retrospective study aimed to describe the effects of convalescent plasma therapy in 24 patients diagnosed with coronavirus disease 2019 (COVID-19) pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during February and March 2020 in Wuhan, China.Materia/MethodsThe confirmation of SARS-CoV-2 infection was made by the reverse transcription-polymerase chain reaction test. We retrospectively analyzed the clinical data and laboratory test reports of patients with severe COVID-19 pneumonia who received a convalescent plasma transfusion.ResultsA total of 24 patients with COVID-19 pneumonia who were transfused with ABO-compatible convalescent plasma were enrolled in the study. Convalescent plasma transfusion showed an effective clinical outcome in 14 of 24 patients (an effective rate of 58.3%). No patients had an adverse reaction to the transfusion. Compared with before convalescent plasma transfusion, the lymphocyte count after convalescent plasma transfusion increased to a normal level (median: 0.80×109/L vs. 1.12×109/L, P=0.004). Other laboratory indicators such as white blood cells, high-sensitivity C-reactive protein, procalcitonin, alanine aminotransferase, and aspartate transaminase showed a decreasing trend after transfusion.ConclusionsThis retrospective observational clinical study showed that convalescent plasma therapy could have beneficial effects on patient outcomes. Recently, regulatory authorization has been given for the use of convalescent plasma therapy, and clinical guidelines have been developed for the collection and use of convalescent plasma and hyperimmune immunoglobulin in patients with COVID-19.

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

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Treatment for COVID-19: An overview

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by coronavirus-2 (SARS-CoV-2) that causes a severe acute respiratory syndrome, a characteristic hyperinflammatory response, vascular damage, microangiopathy, angiogenesis and widespread thrombosis. Four stages of COVID-19 have been identified: the first stage is characterised by upper respiratory tract infection; the second by the onset of dyspnoea and pneumonia; the third by a worsening clinical scenario dominated by a cytokine storm and the consequent hyperinflammatory state; and the fourth by death or recovery. Currently, no treatment can act specifically against the SARS-CoV-2 infection. Based on the pathological features and different clinical phases of COVID-19, particularly in patients with moderate to severe COVID-19, the classes of drugs used are antiviral agents, inflammation inhibitors/antirheumatic drugs, low molecular weight heparins, plasma, and hyperimmune immunoglobulins. During this emergency period of the COVID-19 outbreak, clinical researchers are using and testing a variety of possible treatments. Based on these premises, this review aims to discuss the most updated pharmacological treatments to effectively act against the SARS-CoV-2 infection and support researchers and clinicians in relation to any current and future developments in curing COVID-19 patients.

COVID-19: benefits and risks of passive immunotherapeutics

ABSTRACT Passive immunotherapeutics (PITs), including convalescent plasma, serum, or hyperimmune immunoglobulin, have been of clinical importance during sudden outbreaks since the early twentieth century for the treatment of viral diseases such as severe acute respiratory syndrome (SARS), middle east respiratory syndrome (MERS) and swine flu (H1N1). With the recent SARS-CoV-2 pandemic, wherein effective antivirals and vaccines are still lacking, an interest in convalescent plasma therapy as a lifesaving option has resurfaced due to its capacity for antigenic neutralization and reducing viremia. This review summarizes convalescent blood products (CBPs) in terms of current technologies and the shortcomings related to the collection, manufacture, pathogen inactivation, and banking of CBPs, with a specific focus on their plausible applications, benefits, and risks in the COVID-19 pandemic.

Recruitment Strategy for Potential COVID-19 Convalescent Plasma Donors

Recruitment Strategy for Potential COVID-19 Convalescent Plasma Donors

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

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

Potential Effects of Adjuvant Treatments on Coronavirus Disease 2019 (COVID-19)

At present, there are no effective treatments for coronavirus disease 2019 (COVID-19) and the therapeutic interventions are limited to supportive care, varying from symptomatic management to critical care support. Corticoids are administered to reduce host inflammatory responses in the lungs. The potential harm and the lack of proven benefit of corticosteroids cautions against their routine administration in COVID-19 patients outside the Randomized Clinical Trials (RCTs), with an exception of a concomitant indication, such as a refractory shock. The amplified immune response and Cytokine Release Syndrome (CRS) are known to cause significant organ damage (lungs), providing a rationale for the use of monoclonal Antibody (mAb). Hyperimmune Immunoglobulins (Igs) from the recovered patients may also assist with improving the immune response and virus clearance. Human Normal Immunoglobulins (HNIGs) can be administered in the early seven to ten days of infection, during peak viremia or in the absence of a primary immune response. Ultimately, a vaccine could provide a potential permanent strategy, creating protective immunity for people and preventing future outbreaks. How to cite this article:Tagaev T, Uulu MS, Kyzy AE, Yethindra V, Mainazarova E, Mamatov S et al. Potential Effects of Adjuvant Treatments on Coronavirus Disease 2019 (COVID-19). J Commun Dis 2020; 52(2): 74-77. DOI: https://doi.org/10.24321/0019.5138.202022

Industry call for COVID‐19 convalescent plasma collections

The treatment of COVID-19 patients, especially in severe conditions, presents a challenge to medical professionals. Plasma from recovered COVID-19 patients is a potential and promising therapeutic option, and efforts are underway at different levels to encourage convalescent plasma donations [1, 2]. Convalescent plasma obtained by apheresis from the blood of healthy people who overcame the disease contains specific antibodies against coronavirus SARS-CoV-2. It can be used for immediate transfusion and/or for the manufacture of purified antibodies in the form of polyclonal hyperimmune immunoglobulins. The latter process is lengthy (at least 6 months) and requires large volumes of plasma (at least one thousand litres) for production. Global manufacturers are already working on SARS-CoV-2-specific hyperimmune immunoglobulin therapy options [2]. The success of these efforts requires a sufficient number of donations from willing and eligible patients recovered from COVID-19. It is essential to establish the efficacy of both therapies, as curative and prophylactic treatments in well-thought clinical trials, some of which are already underway [1, 3]. Although the literature on convalescent plasma treatment of COVID-19 is scarce, a few recent publications described positive outcomes in a small number of patients (27 total cases), mainly in critical conditions, who received convalescent plasma from COVID-19 recovered persons [4-8]. Despite limitations, these studies provide supporting evidence for evaluating COVID-19 convalescent plasma in more rigorous investigations. Convalescent plasma is a long-standing therapy that has been used in other infectious and respiratory diseases, including SARS [9]. A large study based on a systematic review and exploratory meta-analysis found that the treatment of SARS patients with convalescent plasma or serum appears to be safe and may reduce mortality rates, especially when administered soon after the disease onset [10]. The U.S. Food and Drug Administration has established a pathway to allow the use of COVID-19 convalescent plasma during the public health emergency [https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma]. The European Commission runs a programme for COVID-19 convalescent plasma collection and transfusion [https://ec.europa.eu/health/blood_tissues_organs/covid-19_en]. However, both activities are limited and do not consider other uses. We posit that COVID-19 convalescent plasma should be collected for immediate transfusions and the manufacturing of hyperimmune immunoglobulin therapies. In addition to COVID-19 survivors who can donate plasma 14 days after complete resolution of symptoms, plasma donation should be encouraged in individuals who tested positive for the SARS-CoV-2 but did not develop COVID-19 after a 14-day incubation period [https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/updated-information-blood-establishments-regarding-novel-coronavirus-covid-19-outbreak]. These asymptomatic individuals, even in the absence of significant knowledge about the levels of SARS-CoV-2 neutralizing antibodies in their blood, may represent a substantial proportion of the infected population and could contribute significantly to the COVID-19 convalescent plasma supply. Once vaccines are developed against SARS-CoV-2 infection, the plasma of vaccinated individuals can be used to produce hyperimmune immunoglobulin therapies of high specificities and titres. Both COVID-19 convalescent plasma and especially hyperimmune immunoglobulin should be considered for pre- and post-exposure treatment for individuals at higher risk for severe illness due to age, poor health and/or other medical conditions, for example abnormalities associated with the immune system function, serious lung pathologies or coagulation disorders. Prophylactic interventions for selected frontline workers with high exposure to infection may allow them to perform critical activities without becoming sick. Medical professionals play an important role in building awareness about the significance of blood and plasma donation as an essential component of the broad healthcare infrastructure. It is highly important to continue informing wide networks about the critical and ongoing need for donations throughout the COVID-19 pandemic and beyond. The need for blood and plasma is greater than ever. On behalf of the standard-setting and global advocacy organization that represents plasma donation centres and manufacturers of plasma protein therapies including human normal and hyperimmune immunoglobulins, we support these efforts with great enthusiasm and appreciation. All authors contributed equally to the writing of this manuscript and approved the final version. Authors report no conflict of interest for this article. Amy Chevalier Efantis, a full-time PPTA employee, declares no funding sources associated with the writing of this manuscript. Brenna Raines, a full-time PPTA employee, declares no funding sources associated with the writing of this manuscript. Larisa Cervenakova, a full-time PPTA employee, declares no funding sources associated with the writing of this manuscript.

Cochrane corner: convalescent plasma or hyperimmune immunoglobulin for people with COVID-19

As the novel coronavirus continues to spread globally and across Africa, efforts are being accelerated to identify effective preventive and therapeutic measures to mitigate its burden. Convalescent plasma and hyperimmune immunoglobulin are being considered as potential therapeutic options for the coronavirus disease 2019 (COVID-19). We highlight and contextualize the findings of a recent Cochrane rapid review that evaluated the effectiveness and safety of convalescent plasma or hyperimmune immunoglobulin transfusion in the treatment of people with COVID-19. From the eight studies it included, the review found limited and low-certainty evidence on the effectiveness and safety of convalescent plasma therapy in patients with COVID-19. The evidence was limited by the small number of participants and low-quality of included studies, as well as the inconsistency of outcome measures and reporting across studies. As African countries brace for the further spread of the virus, while exploring potential therapeutic options to mitigate its morbidity and mortality at peak, convalescent plasma transfusion may offer a therapeutic ray of hope for the continent. Considering the limited evidence of the effectiveness and safety in the treatment of COVID-19, it is imperative for this therapy to be investigated within African contexts to ascertain not only its effectiveness and safety, but also its practical implications within the capacity of national blood transfusion services and health systems in the region.

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

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

Convalescent plasma to treat coronavirus disease 2019 (COVID-19): considerations for clinical trial design.

KEY IDEAS Case series studying convalescent plasma use in the treatment of COVID‐19 have been promising, but additional, high‐quality studies are needed to determine the efficacy of the treatment when applied for prophylaxis, for early phases of illness, and for severe illness.Previous studies of convalescent plasma in treating other viral diseases have identified factors to consider when designing treatment protocols, including timing of administration relative to onset of illness, timing of donation relative to resolution of symptoms, severity of illness of the donor, pretransfusion serology of the recipient, and antibody titers of the donor.There are many clinical trials studying treatment of, and prophylaxis against, COVID‐19 using convalescent plasma. In addition to clinical trials, the FDA also allows treatment through two other pathways: the “Expanded Access to Convalescent Plasma for the Treatment of Patients with COVID‐19” protocol, and emergency investigational new drug applications. The FDA also provides criteria for donation of convalescent plasma.