Factors associated with the SARS-CoV-2 immunoglobulin-G titer levels in convalescent whole-blood donors: a Chinese cross-sectional study.

Blood transfusions from convalescent Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infected patients could be used to treat patients with severe infections or immunocompromised patients. However, it is necessary to select the optimal donors to maximize the utilization of resources. In this study, we investigated the associations among body mass index (BMI), tobacco smoking, exercise frequency and duration, and alcohol consumption with the SARS-CoV-2 immunoglobulin-G (IgG) antibody titer levels with in the Chinese convalescent blood donor population. Here we show that BMI, smoking habits, and exercise frequency appear to be predictive factors for IgG levels in convalescent male blood donors. However, these variables were not observed as predictive of IgG levels in female convalescent blood donors. The findings could be used to optimize the screening for potential blood donors to treat immunocompromised or severely ill COVID-19 patients.

Dosing of Convalescent Plasma and Hyperimmune Anti-SARS-CoV-2 Immunoglobulins: A Phase I/II Dose-Finding Study.

BACKGROUND AND OBJECTIVE: During the COVID-19 pandemic, trials on convalescent plasma (ConvP) were performed without preceding dose-finding studies. This study aimed to assess potential protective dosing regimens by constructing a population pharmacokinetic (popPK) model describing anti-SARS-CoV-2 antibody titers following the administration of ConvP or hyperimmune globulins (COVIg). METHODS: Immunocompromised patients, testing negative for anti-SARS-CoV-2 spike antibodies despite vaccination, received a range of anti-SARS-CoV-2 antibodies in the form of COVIg or ConvP infusion. The popPK analysis was performed using NONMEM v7.4. Monte Carlo simulations were performed to assess potential COVIg and ConvP dosing regimens for prevention of COVID-19. RESULTS: Forty-four patients were enrolled, and data from 42 were used for constructing the popPK model. A two-compartment elimination model with mixed residual error best described the Nab-titers after administration. Inter-individual variation was associated to CL (44.3%), V1 (27.3%), and V2 (29.2%). Lean body weight and type of treatment (ConvP/COVIg) were associated with V1 and V2, respectively. Median elimination half-life was 20 days (interquartile range: 17-25 days). Simulations demonstrated that even monthly infusions of 600 mL of the ConvP or COVIg used in this trial would not achieve potentially protective serum antibody titers for > 90% of the time. However, as a result of hybrid immunity and/or repeated vaccination, plasma donors with extremely high antibody titers are now readily available, and a > 90% target attainment should be possible. CONCLUSION: The results of this study may inform future intervention studies on the prophylactic and therapeutic use of antiviral antibodies in the form of ConvP or COVIg. CLINICAL TRIAL REGISTRATION NUMBER: NL9379 (The Netherlands Trial Register).

Convalescent Plasma Therapy in Immunocompromised Patients Infected With the BA.1 or BA.2 Omicron SARS-CoV-2.

The emergence of SARS-CoV-2 Omicron variant has led to a complete reconfiguration of the therapeutic landscape, with all monoclonal antibodies having lost any neutralization activity. We report here a case series of 75 immunocompromised patients infected by the Omicron variant who benefited from COVID-19 convalescent plasma (CCP). At Day 28, the overall survival was 76% (95% CI 67-86) with no significant difference in the clinical outcome between patients with hematological malignancies, solid organ transplantation or autoimmune diseases. No safety concern was reported during the course of the study. These results showed that CCP is well tolerated and represents a treatment option for immunocompromised patients who remain highly impacted by the COVID19 epidemic.

Charting a path forward: Promising outcomes of convalescent plasma therapy in the care of severely B-cell depleted patients with persistent COVID-19.

BACKGROUND: Patients with severe B-cell depletion related to hematological malignancies or B-cell targeted therapy suffer from impaired antibody responses to SARS-CoV-2 and are at risk for prolonged COVID-19. In this population, COVID-19 convalescent plasma (CCP) may provide passive immunity, enhance immune response, and promote virus neutralization. This study evaluated outcomes of B-cell depleted patients with persistent COVID-19 treated with CCP. STUDY DESIGN AND METHODS: This analysis included all consecutive severely B-cell depleted patients with persistent COVID-19, receiving CCP at Rambam between 01.2022-02.2023. Persistent COVID-19 was defined as the presence of symptoms for ≥14 days in patients with negative SARS-CoV-2 nucleocapsid antibody test results. RESULTS: Twenty patients met inclusion criteria, 17 of whom had hematological malignancies, two suffered from rheumatoid arthritis and one had both. Twelve patients received anti-CD-20 treatment, one - CAR-T cells and three underwent stem cell transplantation. The median duration of COVID-19 symptoms was 27.5 days (range 14-97); 12 patients had mild-to-moderate COVID-19 and 8 had severe infection. Sixteen patients required hospitalization. The majority of patients received other COVID-19 therapies before CCP. Within a median of two days (range 1-16) post-infusion, 19/20 patients clinically improved. No CCP-associated adverse events were documented. COVID-19 symptoms recurred in 3 of the improved patients. Two patients died from COVID-19 on days 1 and 90 following the first CCP infusion. DISCUSSION: In severely B-cell depleted patients with persistent COVID-19, CCP is safe and associated with rapid clinical improvement. This subset of immunocompromised patients could particularly benefit from CCP administration.

The role of graft T-cell size in patients receiving alemtuzumab serotherapy for non-malignant disorders: results of an institutional protocol.

Although graft T cells assist in engraftment, mediate antiviral immune-reconstitution, and cause graft-versus-host disease, graft size is not determined by T-cell content of the graft. The conventional method of graft size determination based on CD34+ cells with alemtuzumab serotherapy is associated with delayed immune reconstitution, contributing to an increased risk of viral infections and graft failure. Alemtuzumab, a long half-life anti-CD52 monoclonal antibody is a robust T-cell depleting serotherapy, and relatively spares memory-effector T cells compared to naïve T cells. We therefore hypothesized that graft size based on T-cell content in patients receiving peripheral blood stem cell graft with alemtuzumab serotherapy would facilitate immune-reconstitution without increasing the risk of graft-versus-host disease. We retrospectively analysed twenty-six consecutive patients with non-malignant disorders grafted using alemtuzumab serotherapy and capping of graft T cells to a maximum of 600 million/kg. The graft T-cell capping protocol resulted in early immune-reconstitution without increasing the risk of severe graft-versus-host disease. Graft T-cell content correlated with CD4+ T-cell reconstitution and acute graft-versus-host disease. The course of CMV viraemia was predictable without recurrence and associated with early T-cell recovery. No patient developed chronic graft-versus-host disease. Overall survival at one year was 100% and disease-free survival was 96% at a median of 899 days (range: 243-1562). Graft size determined by peripheral blood stem cell graft T-cell content in patients receiving alemtuzumab serotherapy for non-malignant disorders is safe and leads to early T-cell immune-reconstitution with excellent survival outcomes.

COVID-19 convalescent plasma therapy decreases inflammatory cytokines: a randomized controlled trial.

IMPORTANCE: This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

[The burden of COVID-19 in a heterogeneous population of immunocompromised patients - realities of the postpandemic].

On July 3, 2023, an interdisciplinary Council of Experts "The burden of COVID-19 in a heterogeneous population of immunocompromised patients - post-pandemic realities" was held in Moscow with leading experts in pulmonology, rheumatology, hematology, oncology, nephrology, allergology-immunology, transplantation, and infectious diseases. The aim of the meeting was to discuss the current clinical and epidemiologic situation related to COVID-19, the relevance of disease prevention strategies for high-risk patients. The experts addressed the following issues: 1) the disease burden of COVID-19 in 2023 for patients with immunodeficiency in different therapeutic areas; 2) the place of passive immunization with monoclonal antibodies as a method of COVID-19 prophylaxis among immunocompromised patients; 3) prerequisites for the inclusion of passive immunization of immunocompromised patients into routine clinical practice.

Mechanisms and research advances in mRNA antibody drug-mediated passive immunotherapy.

Antibody technology is widely used in the fields of biomedical and clinical therapies. Nonetheless, the complex in vitro expression of recombinant proteins, long production cycles, and harsh storage conditions have limited their applications in medicine, especially in clinical therapies. Recently, this dilemma has been overcome to a certain extent by the development of mRNA delivery systems, in which antibody-encoding mRNAs are enclosed in nanomaterials and delivered to the body. On entering the cytoplasm, the mRNAs immediately bind to ribosomes and undergo translation and post-translational modifications. This process produces monoclonal or bispecific antibodies that act directly on the patient. Additionally, it eliminates the cumbersome process of in vitro protein expression and extends the half-life of short-lived proteins, which significantly reduces the cost and duration of antibody production. This review focuses on the benefits and drawbacks of mRNA antibodies compared with the traditional in vitro expressed antibodies. In addition, it elucidates the progress of mRNA antibodies in the prevention of infectious diseases and oncology therapy.

Understanding Infection Risk with Anti-BCMA Bispecific Antibodies.

SUMMARY: Lancman and colleagues find that infection risk in patients treated with anti-BCMA bispecific antibodies for relapsed/refractory multiple myeloma is associated with severe immunoglobulin deficiency and may be mitigated by immunoglobulin replacement therapy. The study has implications for managing infection risk and raises questions about the optimal duration of treatment with these potent, novel immunotherapies. See related article by Lancman et al., p. 440 (4) .

Animal Toxins: A Historical Outlook at the Institut Pasteur of Paris.

Humans have faced poisonous animals since the most ancient times. It is recognized that certain animals, like specific plants, produce toxic substances that can be lethal, but that can also have therapeutic or psychoactive effects. The use of the term "venom", which initially designated a poison, remedy, or magic drug, is now confined to animal poisons delivered by biting. Following Louis Pasteur's work on pathogenic microorganisms, it was hypothesized that venoms could be related to bacterial toxins and that the process of pathogenicity attenuation could be applied to venoms for the prevention and treatment of envenomation. Cesaire Phisalix and Gabriel Bertrand from the National Museum of Natural History as well as Albert Calmette from the Institut Pasteur in Paris were pioneers in the development of antivenomous serotherapy. Gaston Ramon refined the process of venom attenuation for the immunization of horses using a formalin treatment method that was successful for diphtheria and tetanus toxins. This paved the way for the production of antivenomous sera at the Institut Pasteur, as well as for research on venom constituents and the characterization of their biological activities. The specific activities of certain venom components, such as those involved in blood coagulation or the regulation of chloride ion channels, raises the possibility of developing novel therapeutic drugs that could serve as anticoagulants or as a treatment for cystic fibrosis, for example. Scientists of the Institut Pasteur of Paris have significantly contributed to the study of snake venoms, a topic that is reported in this review.

Serum anti-Spike immunoglobulin G levels in random blood donors in Italy: High-titre convalescent plasma is easier than ever to procure.

BACKGROUND AND OBJECTIVES: COVID-19 convalescent plasma (CCP) has retained potency and clinical efficacy against SARS-CoV-2 and is currently of utmost value for seronegative immunocompromised patients. Since most of the effect is due to the vaccine boost of infection-elicited antibodies, there is a theoretical concern that the frequency of suitable donors is declining. MATERIALS AND METHODS: In this single-institution serosurvey, we screened 599 consecutive donors attending our area in two different seasons (300 in November 2022 and 299 in February 2023) using the Abbott Alinity® anti-Spike immunoglobulin G assay. RESULTS: More than 80% of random donors qualify according to the FDA criteria for high-titre CCP (>4350 AU/mL), with a stable trend. CONCLUSION: Despite reduced anti-Spike vaccine boost deployment in the general population, we have shown here that high-titre CCP units are easier than ever to procure. This finding also has implications for the derivation of standard immunoglobulins, which are finally approaching the potency of hyperimmune serum and could soon represent an alternative to CCP.

Recommendations for Management of Secondary Antibody Deficiency in Multiple Myeloma.

Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor antibody function. SAD is common in patients with multiple myeloma (MM) due to underlying disease pathophysiology and treatment-related immune system effects. Patients with SAD are more susceptible to infections and infection-related morbidity and mortality. With therapeutic advancements improving MM disease control and survival, it is increasingly important to recognize and treat the often-overlooked concurrent immunodeficiency present in patients with MM. The aims of this review are to define SAD and its consequences in MM, increase SAD awareness, and provide recommendations for SAD management. Based on expert panel discussions at a standalone meeting and supportive literature, several recommendations were made. Firstly, all patients with MM should be suspected to have SAD regardless of serum antibody concentrations. Patients should be evaluated for immunodeficiency at MM diagnosis and stratified into management categories based on their individualized risk of SAD and infection. Infection-prevention strategy education, early infection reporting, and anti-infective prophylaxis are key. We recommend prophylactic antibiotics or immunoglobulin replacement therapy (IgRT) should be considered in patients with severe hypogammaglobulinemia associated with a recurrent or persistent infection. To ensure an individualized and efficient treatment approach is utilized, patient's immunoglobin G concentration and infection burden should be closely monitored throughout treatment. Patient choice regarding route and IgRT treatment is also key in reducing treatment burden. Together, these recommendations and proposed management algorithms can be used to aid physician decision-making to improve patient outcomes.

Passive pre-exposure immunization by tixagevimab/cilgavimab in patients with hematological malignancy and COVID-19: matched-paired analysis in the EPICOVIDEHA registry.

Only few studies have analyzed the efficacy of tixagevimab/cilgavimab to prevent severe Coronavirus disease 2019 (COVID-19) and related complications in hematologic malignancies (HM) patients. Here, we report cases of breakthrough COVID-19 after prophylactic tixagevimab/cilgavimab from the EPICOVIDEHA registry). We identified 47 patients that had received prophylaxis with tixagevimab/cilgavimab in the EPICOVIDEHA registry. Lymphoproliferative disorders (44/47, 93.6%) were the main underlying HM. SARS-CoV-2 strains were genotyped in 7 (14.9%) cases only, and all belonged to the omicron variant. Forty (85.1%) patients had received vaccinations prior to tixagevimab/cilgavimab, the majority of them with at least two doses. Eleven (23.4%) patients had a mild SARS-CoV-2 infection, 21 (44.7%) a moderate infection, while 8 (17.0%) had severe infection and 2 (4.3%) critical. Thirty-six (76.6%) patients were treated, either with monoclonal antibodies, antivirals, corticosteroids, or with combination schemes. Overall, 10 (21.3%) were admitted to a hospital. Among these, two (4.3%) were transferred to intensive care unit and one (2.1%) of them died. Our data seem to show that the use of tixagevimab/cilgavimab may lead to a COVID-19 severity reduction in HM patients; however, further studies should incorporate further HM patients to confirm the best drug administration strategies in immunocompromised patients.

Cell-to-cell spread inhibiting antibodies constitute a correlate of protection against herpes simplex virus type 1 reactivations: A retrospective study.

Background: Herpes simplex viruses (HSV) cause ubiquitous human infections. For vaccine development, knowledge concerning correlates of protection is essential. Therefore, we investigated (I) if humans are in principle capable producing cell-to-cell spread inhibiting antibodies against HSV and (II) whether this capacity is associated with a reduced HSV-1 reactivation risk. Methods: We established a high-throughput HSV-1-ΔgE-GFP reporter virus-based assay and evaluated 2,496 human plasma samples for HSV-1 glycoprotein E (gE) independent cell-to-cell spread inhibiting antibodies. Subsequently, we conducted a retrospective survey among the blood donors to analyze the correlation between the presence of cell-to-cell spread inhibiting antibodies in plasma and the frequency of HSV reactivations. Results: In total, 128 of the 2,496 blood donors (5.1%) exhibited high levels of HSV-1 gE independent cell-to-cell spread inhibiting antibodies in the plasma. None of the 147 HSV-1 seronegative plasmas exhibited partial or complete cell-to-cell spread inhibition, demonstrating the specificity of our assay. Individuals with cell-to-cell spread inhibiting antibodies showed a significantly lower frequency of HSV reactivations compared to subjects without sufficient levels of such antibodies. Conclusion: This study contains two important findings: (I) upon natural HSV infection, some humans produce cell-to-cell spread inhibiting antibodies and (II) such antibodies correlate with protection against recurrent HSV-1. Moreover, these elite neutralizers may provide promising material for immunoglobulin therapy and information for the design of a protective vaccine against HSV-1.

Convalescent Plasma Treatment of Patients Previously Treated with B-Cell-Depleting Monoclonal Antibodies Suffering COVID-19 Is Associated with Reduced Re-Admission Rates.

Patients receiving treatment with B-cell-depleting monoclonal antibodies, such as anti-CD20 monoclonal antibodies, such as rituximab and obinutuzumab, either for hematological disease or another diagnosis, such as a rheumatological disease, are at an increased risk for medical complications and mortality from COVID-19. Since inconsistencies persist regarding the use of convalescent plasma (CP), especially in the vulnerable patient population that has received previous treatment with B-cell-depleting monoclonal antibodies, further studies should be performed in thisdirection. The aim of the present study was to describe the characteristics of patients with previous use of B-cell-depleting monoclonal antibodies and describe the potential beneficial effects of CP use in terms of mortality, ICU admission and disease relapse. In this retrospective cohort study, 39 patients with previous use of B-cell-depleting monoclonal antibodies hospitalized in the COVID-19 department of a tertiary hospital in Greece were recorded and evaluated. The mean age was 66.3 years and 51.3% were male. Regarding treatment for COVID-19, remdesivir was used in 89.7%, corticosteroids in 94.9% and CP in 53.8%. In-hospital mortality was 15.4%. Patients who died were more likely to need ICU admission and also had a trend towards a longer hospital stay, even though the last did not reach statistical significance. Patients treated with CP had a lower re-admission rate for COVID-19 after discharge. Further studies should be performed to identify the role of CP in patients with treatment with B-cell-depleting monoclonal antibodies suffering from COVID-19.

Allele mining in gene encoding fc fragment of IgG receptor, transporter, alpha (FCGRT) and association of nucleotide variants with passive transfer of immunity in neonatal buffalo calves.

BACKGROUND: Neonatal Fc receptors (FcRn) mediate the transcytosis of IgG present in colostrum across absorptive gut epithelium of newborn calves. FcRn receptor is a heterodimer composed of two polypeptides encoded by FCGRT (Fc fragment of IgG Receptor Transporter neonatal) and B2M (Beta 2 microglobulin) genes. Polymorphism in FCGRT gene may have a bearing on absorption of colostral immunoglobulins by neonatal buffalo calves, thereby affecting their immune status and susceptibility to diseases. The primary aim of our study was to mine alleles and single nucleotide polymorphs in the FCGRT gene and determine their association with the levels of IgG in serum of neonatal buffalo calves. METHODS AND RESULTS: On the basis of serum IgG levels estimated by indirect ELISA in 80 newborn calves, 20 calves each with highest and lowest IgG concentration were selected to study polymorphism in the FCGRT gene. The exonic regions of this gene were amplified in nine fragments which were subjected to PCR-SSCP to detect variations followed by the sequencing of variants to locate the SNPs. A total of nine SNPs (7 in introns and 2 in exons) were detected in four polymorphic fragments. Association study based on Odds ratios (ORs) with 95% Confidence Interval (CIs) established that the SNP G40T in fragment 3 has a significant (P < 0.05) bearing on IgG level in serum of neonatal buffalo calves. CONCLUSION: Genetic variation in FCGRT gene in buffalo calves was found to be associated with their serum IgG levels in neonatal stage which may have implications in calf survival and growth vis-à-vis inadequate transfer of passive immunity.

Cytomegalovirus immunoglobulin therapy for CMV retinitis post hematopoietic stem cell transplantation.

PURPOSE: To report a case of cytomegalovirus (CMV) retinitis complicated with ganciclovir-related myelosuppression, which was successfully managed with intravenous (IV) ganciclovir and CMV immunoglobulin (CMVIG) therapy. METHODS: Observational case report. RESULTS: A 51-year-old male with follicular type non-Hodgkin lymphoma post hematopoietic stem cell transplantation (HSCT) developed vision-threatening retinitis. polymerase chain reaction (PCR) of the aqueous humour showed positive for CMV. Despite myelosuppression occurred during IV ganciclovir therapy, the retinitis resolved and intraocular CMV viral load significantly improved after CMVIG therapy. CONCLUSION: Combined IV ganciclovir treatment and CMVIG therapy can significantly improve visual outcome and reduce intraocular CMV viral load in vision-threatening CMV retinitis.

Beyond COVID-19 and lessons learned in the United States.

The COVID-19 pandemic severely tested the resilience of the US blood supply with wild fluctuations in blood donation and utilisation rates as community donation opportunities ebbed and hospitals post-poned elective surgery. Key stakeholders in transfusion services, blood centres, supply chains and manufacturers reviewed their experiences during the SARS-CoV-2 pandemic as well as available literature to describe successes, opportunities for improvement and lessons learned. The blood community found itself in uncharted territory responding to restriction of its access to donors (approximately 20% decrease) and some supplies; environmental adjustments to address staff and donor concerns about coronavirus transmission; and the development of a new product (COVID-19 convalescent plasma [CCP]). In assuring that the needs of the patients were paramount, the donation process was safe, that clinicians had access to CCP, and vendor relationships aligned, the blood banking community relearned its primary focus: improving patient outcomes.

Convalescent plasma and COVID-19: Time for a second-second look?

In this short narrative, we highlight some of our experiences leading the US Convalescent Plasma Program at the beginning of the pandemic in the spring and summer of 2020. This includes a brief summary of how the program emerged and high-level lessons we learned. We also share our impressions about why convalescent plasma was used at scale in the United States, early in the pandemic and share ideas that might inform the use of convalescent plasma in future outbreaks of novel infectious diseases.