Convalescent anti-SARS-CoV-2 plasma for the treatment of patients with COVID-19: a retrospective study RESCOVID-19.

PURPOSE: Convalescent plasma (CP) collected from people who recovered from COVID-19 became a rapidly available treatment modality in numerous countries, including the Czech Republic. The aims of our study were to evaluate the effectiveness and safety of CP in the treatment of COVID-19. METHODS: This retrospective observational study involved six Czech hospitals. This study enrolled patients with and without CP treatment who were hospitalized between April 2020 and April 2021. Propensity score matching and logistic regression analysis were performed to evaluate the influence of CP administration and its timing on the in-hospital survival of COVID-19 patients. RESULTS: A total of 1,498 patients were enrolled in the study; 406 (27%) were administered CP, and 1,092 (73%) were not treated with CP. The propensity score-matched control group consisted of 1,218 subjects. The survival of patients treated with CP was 79%, while that of patients in the matched control group was 62% (P<0.001). Moreover, the chance of survival was significantly greater when CP was administered within three days after the onset of COVID-19 symptoms than when CP was administered after four or more days (87% vs. 76%, P <0.001). In addition, adverse effects related to CP administration were recorded in only 2% of patients and were considered mild in all patients. CONCLUSIONS: Our study demonstrated that the administration of CP was safe and possibly associated with positive effects that were more pronounced if CP was administered within the first three days after the onset of COVID-19 symptoms.

Estimates of actual and potential lives saved in the United States from the use of COVID-19 convalescent plasma.

In the Spring of 2020, the United States of America (USA) deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Over 500,000 patients were treated with CCP during the first year of the pandemic. In this study, we estimated the number of actual inpatient lives saved by CCP treatment in the United States of America based on CCP weekly use, weekly national mortality data, and CCP mortality reduction data from meta-analyses of randomized controlled trials and real-world data. We also estimate the potential number of lives saved if CCP had been deployed for 100% of hospitalized patients or used in 15 to 75% of outpatients. Depending on the assumptions modeled in stratified analyses, we estimated that CCP saved between 16,476 and 66,296 lives. The CCP ideal use might have saved as many as 234,869 lives and prevented 1,136,133 hospitalizations. CCP deployment was a successful strategy for ameliorating the impact of the COVID-19 pandemic in the USA. This experience has important implications for convalescent plasma use in future infectious disease emergencies.

Assessment of immunological factors in COVID-19 patients treated by convalescent plasma.

Following the outbreak of COVID-19, several immunotherapy methods were used to modulate the immune responses of patients. In this study, we aimed to evaluate the immune response to COVID-19 in patients receiving convalescent plasma. In this regard, this randomized controlled trial included 30 patients who were divided into two groups according to receiving convalescent plasma or normal control plasma. Samples from both groups were collected on days 0, 1, 3, 5 and 7 after plasma infusion. We measured the expression level of TLR7/8, IRF3/7, CTLA-4, PD-1 and T cell transcription factors by Real-time PCR in the mentioned groups. Thirteen cytokines were also evaluated using flow cytometry method. Results showed that compared to the normal control plasma group, the expression levels of TLR7, 8, IRF3, 7 and PD-1 and CTLA-4, on days 3, 5 and 7 after convalescent plasma infusion, were significantly decreased. On the other hand,  Gene expression results showed that the expression levels of Tbet, RORγ3 and Foxp3 on days 3, 5 and 7 after convalescent plasma infusion were significantly increased compared to the normal control plasma group. After convalescent plasma infusion, the viral load was significantly decreased compared to the normal control plasma group. Convalescent plasma infusion also reduced the plasma cytokines levels, including IL-6, IL-10, and IL-4, and enhanced the level of IL-2, IFN- γ and perforin comparing the normal control plasma group. According to the results, the convalescent plasma infusion led to a decrease in the expression of innate immunity receptors and an increase in the expression of transcription factors of adaptive immunity. Therefore, it may be concluded that convalescent plasma infusion can modulate the immune response. To achieve a reliable consequence, further studies are required.

Antibody-mediated protection against respiratory syncytial virus in children.

Respiratory syncytial virus (RSV) is a major global pathogen, causing lower respiratory tract disease in at-risk populations including young children. Antibodies form a crucial layer of protection from RSV disease, particularly in immunologically naïve infants. Such antibodies are derived from the mother via transplacental transfer and breast milk, but may be particularly low in high-risk infants such as those born preterm. Maternally derived antibodies can now be supplemented by the administration of anti-RSV monoclonal antibodies, while a rising wave of maternal and paediatric vaccine strategies are approaching. The implementation of these prophylactics may profoundly decrease the healthcare burden of RSV. In this article, we review the role of antibody-mediated immunity in protecting children from RSV. We focus on maternally derived antibodies as the main source of protection against RSV and study factors that influence the scale of this transfer. The role of passive and active prophylactic approaches in protecting infants against RSV are discussed and knowledge gaps in our understanding of antibody-mediated protection against RSV are identified.

Efficacy of convalescent plasma in hospitalized COVID-19 patients: findings from a controlled trial.

The COVID-19 pandemic has driven the search for alternative therapies, including convalescent plasma, historically used in infectious diseases. Despite results in other diseases, its effectiveness against COVID-19 remains uncertain with conflicting results in clinical trials. A pragmatic, single-center, prospective, and open randomized controlled trial was carried out in a hospital in Brazil, with the aim of evaluating the impact of convalescent plasma on the clinical improvement of patients hospitalized with COVID-19. The World Health Organization (WHO) ordinal scale was used to measure clinical improvement, focusing on the reduction in disease severity by up to 2 points, while antibody and C-reactive protein levels were monitored over time. After hospital admission, participants were randomized 1:1 to receive convalescent plasma and standard treatment or to be part of the control group with standard treatment. Follow-up was carried out on days 1, 3, 7, 14 and/or at discharge. From January 14 to April 4, 2022, 38 patients were included, but 3 were excluded due to protocol deviations, resulting in a total of 35 patients: 19 in the control group and 16 in the plasma group. There was no significant difference in clinical improvement between the convalescent plasma group and the control group, nor in secondary outcomes. The study had limitations due to the small number of patients and limited representation of COVID-19 cases. Broader investigations are needed to integrate therapies into medical protocols, both for COVID-19 and other diseases. Conducting randomized studies is challenging due to the complexity of medical conditions and the variety of treatments available.

Biochemical rationale for transfusion of high titre COVID-19 convalescent plasma.

We aimed to model binding of donor antibodies to virus that infects COVID-19 patients following transfusion of convalescent plasma (CCP). An immunosorbent assay was developed to determine apparent affinity (Kd, app). Antibody binding to virus was modelled using antibody concentration and estimations of viral load. Assay and model were validated using reference antibodies and clinical data of monoclonal antibody therapy. A single Kd, app or two resolvable Kd, app were found for IgG in 11% or 89% of CCP donations, respectively. For IgA this was 50%-50%. Median IgG Kd, app was 0.8nM and 3.6nM for IgA, ranging from 0.1-14.7nM and 0.2-156.0nM respectively. The median concentration of IgG was 44.0nM (range 8.4-269.0nM) and significantly higher than IgA at 2.0nM (range 0.4-11.4nM). The model suggested that a double CCP transfusion (i.e. 500 mL) allows for > 80% binding of antibody to virus provided Kd, app was < 1nM and concentration > 150nM. In our cohort from the pre-vaccination era, 4% of donations fulfilled these criteria. Low and mid-range viral loads are found early post exposure, suggesting that convalescent plasma will be most effective then. This study provides a biochemical rationale for selecting high affinity and high antibody concentration CCP transfused early in the disease course.

The role of convalescent plasma and hyperimmune immunoglobulins in the COVID-19 pandemic, including implications for future preparedness.

Introduction: When Coronavirus Disease-19 (COVID-19) struck the world in December 2019, initiatives started to investigate the efficacy of convalescent plasma, a readily available source of passive antibodies, collected from recovered patients as a therapeutic option. This was based on historical observational data from previous virus outbreaks. Methods: A scoping review was conducted on the efficacy and safety of convalescent plasma and hyperimmune immunoglobulins for COVID-19 treatment. This review included the latest Cochrane systematic review update on 30-day mortality and safety. We also covered use in pediatric and immunocompromised patients, as well as the logistic challenges faced in donor recruitment and plasma collection in general. Challenges for low resource countries were specifically highlighted. Results: A major challenge is the high donation frequency required from first-time donors to ensure a safe product, which minimizes the risk of transfusion-transmitted infectious. This is particularly difficult in low- and middle- income countries due to inadequate infrastructure and insufficient blood product supplies. High-certainty evidence indicates that convalescent plasma does not reduce mortality or significantly improve clinical outcomes in patients with moderate to severe COVID-19 infection. However, CCP may provide a viable treatment for patients unable to mount an endogenous immune response to SARS-CoV-2, based on mostly observational studies and subgroup data of published and ongoing randomized trials. Convalescent plasma has been shown to be safe in adults and children with COVID-19 infection. However, the efficacy in pediatric patients remains unclear. Discussion: Data on efficacy and safety of CCP are still underway in ongoing (randomized) studies and by reporting the challenges, limitations and successes encountered to-date, research gaps were identified to be addressed for the future. Conclusion: This experience serves as a valuable example for future pandemic preparedness, particularly when therapeutic options are limited, and vaccines are either being developed or ineffective due to underlying immunosuppression.

Potential immunomodulatory effects of CAS+IMD monoclonal antibody cocktail in hospitalized patients with COVID-19.

BACKGROUND: Passive administration of SARS-CoV-2 neutralizing monoclonal antibodies (mAbs), such as CAS + IMD (Casirivimab + Imdevimab) antibody cocktail demonstrated beneficial effects on clinical outcomes in hospitalized patients with COVID-19 who were seronegative at baseline and outpatients. However, little is known about their impact on the host immunophenotypes. METHODS: We conducted an immunoprofiling study in 46 patients from a single site of a multi-site trial of CAS + IMD in hospitalized patients. We collected longitudinal samples during October 2020 âˆ¼ April 2021, prior to the emergence of the Delta and Omicron variants and the use of COVID-19 vaccines. All collected samples were analyzed without exclusion and post-hoc statistical analysis was performed. We examined the dynamic interplay of CAS + IMD with host immunity applying dimensional reduction approach on plasma proteomics and high dimensional flow cytometry data. FINDINGS: Using an unbiased clustering method, we identified unique immunophenotypes associated with acute inflammation and disease resolution. Compared to placebo group, administration of CAS + IMD accelerated the transition from an acute inflammatory immunophenotype, to a less inflammatory or "resolving" immunophenotype, as characterized by reduced tissue injury, proinflammatory markers and restored lymphocyte/monocyte imbalance independent of baseline serostatus. Moreover, CAS + IMD did not impair the magnitude or the quality of host T cell immunity against SARS-CoV-2 spike protein. INTERPRETATION: Our results identified immunophenotypic changes indicative of a possible SARS-CoV-2 neutralizing antibodies-induced anti-inflammatory effect, without an evident impairment of cellular antiviral immunity, suggesting that further studies of Mabs effects on SAS-CoV-2 or other viral mediated inflammation are warranted. FUNDING: Regeneron Pharmaceuticals Inc and federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority, under OT number: HHSO100201700020C.

Immunoglobulin therapy for immunodeficiency.

Immunoglobulin replacement is donor-derived pooled immunoglobulin G, which provides passive immunity to patients with antibody deficiency or dysfunction. It may be administered via either intravenous or subcutaneous routes. Intravenous immunoglobulin is administered at higher doses every 3-4 weeks, whereas most forms of subcutaneous immunoglobulin are administered at lower doses, usually every 1-2 weeks. Benefits and risks, including adverse effects, convenience, and cost vary according to route of administration. Immunoglobulin products also differ in their composition, so patient-specific comorbidities are important to consider when selecting an immunoglobulin product. We discuss adverse effects associated with immunoglobulin therapy, their associated risk factors, treatment, and ways to mitigate these risks. Finally, the laboratory monitoring and vaccination recommendations for patients on immunoglobulin replacement therapy are reviewed.

SARS-CoV-2 infection vs. vaccination during pregnancy: the placenta leads the way.

PURPOSE OF REVIEW: To understand the characteristics and determinants of transplacental antibody transfer against SARS-CoV-2 and to compare the differences between SARS-CoV-2 infection and vaccination. RECENT FINDINGS: The need for information during the COVID-19 pandemic and the exclusion of pregnant women from randomized clinical trials have led to a vast amount of clinical data primarily based on observational studies with diverse design and sample analyses that yield variable results. This review aims to critically and comprehensively integrate the relevant knowledge related to transplacental transfer of antibodies against SARS-CoV-2, emphasizing the differences between infection and vaccination. SUMMARY: Passive immunization is key to conferring protection to the infant during their first months of life. Understanding the mechanisms of transplacental antibody transfer during SARS-CoV-2 infection and vaccination, and their associated protection will allow optimizing the implementation of well tolerated and effective preventive strategies for both pregnant women and infants.

Descriptions of Scientific Evidence and Uncertainty of Unproven COVID-19 Therapies in US News: Content Analysis Study.

BACKGROUND: Politicization and misinformation or disinformation of unproven COVID-19 therapies have resulted in communication challenges in presenting science to the public, especially in times of heightened public trepidation and uncertainty. OBJECTIVE: This study aims to examine how scientific evidence and uncertainty were portrayed in US news on 3 unproven COVID-19 therapeutics, prior to the development of proven therapeutics and vaccines. METHODS: We conducted a media analysis of unproven COVID-19 therapeutics in early 2020. A total of 479 discussions of unproven COVID-19 therapeutics (hydroxychloroquine, remdesivir, and convalescent plasma) in traditional and online US news reports from January 1, 2020, to July 30, 2020, were systematically analyzed for theme, scientific evidence, evidence details and limitations, safety, efficacy, and sources of authority. RESULTS: The majority of discussions included scientific evidence (n=322, 67%) although only 24% (n=116) of them mentioned publications. "Government" was the most frequently named source of authority for safety and efficacy claims on remdesivir (n=43, 35%) while "expert" claims were mostly mentioned for convalescent plasma (n=22, 38%). Most claims on hydroxychloroquine (n=236, 79%) were offered by a "prominent person," of which 97% (n=230) were from former US President Trump. Despite the inclusion of scientific evidence, many claims of the safety and efficacy were made by nonexperts. Few news reports expressed scientific uncertainty in discussions of unproven COVID-19 therapeutics as limitations of evidence were infrequently included in the body of news reports (n=125, 26%) and rarely found in headlines (n=2, 2%) or lead paragraphs (n=9, 9%; P<.001). CONCLUSIONS: These results highlight that while scientific evidence is discussed relatively frequently in news reports, scientific uncertainty is infrequently reported and rarely found in prominent headlines and lead paragraphs.

RSV Prevention Within Reach for Older Infants and Toddlers: The Role of Active Immunization.

This review article will summarize the vaccines and monoclonal antibodies currently under evaluation for the prevention of RSV disease in older infants, toddlers and young children. We will review the rationale for passive protection during the first months of life, and the role of active immunization afterwards, either with live attenuated, protein-based or mRNA vaccines.

Differential polyvalent passive immune protection of egg yolk antibodies (IgY) against live and inactivated Vibrio fluvialis in fish.

Egg yolk antibodies (IgY) can be prepared in large quantities and economically, and have potential value as polyvalent passive vaccines (against multiple bacteria) in aquaculture. This study prepared live and inactivated Vibrio fluvialis IgY and immunized Carassius auratus prior to infection with V. fluvialis and Aeromonas hydrophila. The results showed that the two IgY antibodies hold effective passive protective rates against V. fluvialis and A. hydrophila in C. auratus. Further, the serum of C. auratus recognized the two bacteria in vitro, with a decrease in the bacteria content of the kidney. The phagocytic activity of C. auratus plasma was enhanced, with a decrease in the expression of inflammatory and antioxidant factors. Pathological sections showed that the kidney, spleen, and intestinal tissue structures were intact, and apoptosis and DNA damage decreased in kidney cells. Moreover, the immunoprotection conferred by the live V. fluvialis IgY was higher than that of the inactivated IgY. Addition, live V. fluvialis immunity induced IgY antibodies against outer membrane proteins of V. fluvialis were more than inactivated V. fluvialis immunity. Furthermore, heterologous immune bacteria will not cause infection, so V. fluvialis can be used to immunize chickens to obtain a large amount of IgY antibody. These findings suggest that the passive immunization effect of live bacterial IgY antibody on fish is significantly better than that of inactivated bacterial antibody, and the live V. fluvialis IgY hold potential value as polyvalent passive vaccines in aquaculture.

Passive immunization of mice with IgY anti-H5N1 protects against experimental influenza virus infection and allows development of protective immunity.

Influenza virus contributes substantially to the global human and animal disease burden. To protect individuals against disease, strategies are needed to minimize the time an individual is at risk of developing disease symptoms. Passive immunization using avian IgY antibodies can protect individuals against a variety of pathogens, including influenza virus. Yet the effect of IgY administration on generation of protective immunity is largely unknown. To address the effect of passive immunization on the host immune response development, adult or aged, male and female C57BL/6NCrl mice received chicken IgY anti-H5N1, normal IgY or PBS intranasally four hours before, and 20 hours after intranasal infection with H1N1 influenza A virus (PR8). The mice receiving cross-reactive IgY anti-H5N1 were protected from disease and developed influenza virus-specific memory T cells similar to control-treated mice. When re-challenged with PR8 35 days post primary infection IgY anti-H5N1-treated mice were fully protected. Moreover, when challenged with heterologous H3N2 influenza A virus (X-31) or with PR8 three months post infection the mice were protected against severe disease and death, albeit a slight transient weight loss was noted. The results show that passive immunization with IgY anti-H5N1 is safe and protects mice against disease induced by influenza virus without inhibiting development of protective immunity after virus exposure. This indicate that passive immunization can be used as prophylactic therapy in combination with immunization to prevent disease.

Extended remdesivir administration in haematological patients with malignancies and COVID-19 during the Omicron era: safety and outcomes.

OBJECTIVES: To describe the management of haematological patients experiencing prolonged SARS-CoV-2 viral shedding, as the optimal management strategy for this condition remains undetermined. METHODS: We conducted a retrospective evaluation of our prospectively followed cohort of haematological patients treated with remdesivir for more than 10 days. Starting January 2023, upon COVID-19 diagnosis, the treatment strategy was based on symptoms and PCR cycle threshold (Ct) as follows: (i) when Ct was 25 or less or if the patient had symptoms, a course of remdesivir for at least 10 days, nirmatrelvir/ritonavir for 5 days (whenever possible) and convalescent plasma was administered; and (ii) when the patient was asymptomatic and had a PCR Ct of more than 25, when possible, a course of 5 days of nirmatrelvir/ritonavir was administered. The patient was considered to have achieved viral clearance and, thus, remdesivir was stopped, in either of these cases: (i) PCR negativity, or (ii) subgenomic RNA negativity. RESULTS: From January to November 2023, 18 patients benefited from a safe extended remdesivir administration, resulting in detection of SARS-CoV-2 viral clearance in a median time of 3.5 weeks (IQR 2.6-3.9) (min-max 1.6-8.0). No clinical or biological side effects were detected. No patient died or needed further treatment for their COVID-19 episode. CONCLUSIONS: The extended course of remdesivir, combined with other active therapies for COVID-19 infection, was well tolerated. Cure and virus negativity were obtained in all these high-risk patients.

Influence of AAV vector tropism on long-term expression and Fc-γ receptor binding of an antibody targeting SARS-CoV-2.

Long-acting passive immunization strategies are needed to protect immunosuppressed vulnerable groups from infectious diseases. To further explore this concept for COVID-19, we constructed Adeno-associated viral (AAV) vectors encoding the human variable regions of the SARS-CoV-2 neutralizing antibody, TRES6, fused to murine constant regions. An optimized vector construct was packaged in hepatotropic (AAV8) or myotropic (AAVMYO) AAV capsids and injected intravenously into syngeneic TRIANNI-mice. The highest TRES6 serum concentrations (511 µg/ml) were detected 24 weeks after injection of the myotropic vector particles and mean TRES6 serum concentrations remained above 100 µg/ml for at least one year. Anti-drug antibodies or TRES6-specific T cells were not detectable. After injection of the AAV8 particles, vector mRNA was detected in the liver, while the AAVMYO particles led to high vector mRNA levels in the heart and skeletal muscle. The analysis of the Fc-glycosylation pattern of the TRES6 serum antibodies revealed critical differences between the capsids that coincided with different binding activities to murine Fc-γ-receptors. Concomitantly, the vector-based immune prophylaxis led to protection against SARS-CoV-2 infection in K18-hACE2 mice. High and long-lasting expression levels, absence of anti-drug antibodies and favourable Fc-γ-receptor binding activities warrant further exploration of myotropic AAV vector-based delivery of antibodies and other biologicals.

Economic impact of immunoglobulin replacement therapy in secondary immunodeficiency to hematological cancer: a single center observational study.

This is the first report of the health economic benefits derived from preventing infections through Immunoglobulin Replacement Therapy (IgRT) in patients with secondary immunodeficiency due to hematological malignancies. We conducted a retrospective population-based cohort study using patient medical history and pharmacy data from the Hospital Clínico San Carlos for 21 patients between 2011 and 2020. The pharmacoeconomic impact of using prophylactic IgRT was assessed by comparing characteristics of the SID patients 1 year before and after initiating IgRT measured by direct medical and tangible indirect costs. Results indicate a marked reduction in hospitalization days following IgRT initiation, decreasing from an average of 13.9 to 6.1 days per patient, with the elimination of ICU admissions. While emergency department visits decreased significantly, the number of routine consultations remained unchanged. Notably, absenteeism from work dropped substantially. The financial analysis revealed significant reductions in medication use and fewer ancillary tests, resulting in considerable cost savings. Specifically, total expenditure dropped from €405,088.18 pre-IgRT to €295,804.42 post-IgRT-including the cost of IgRT itself at €156,309.60. Overall, the annual savings amounted to €109,283.84, validating the cost-effectiveness of IgRT in managing SID in patients with hematological cancers.

Passive Immunization Strategies to Prevent Severe Respiratory Syncytial Virus Infection Among Newborns and Young Infants.

Newborns and young infants are at risk for severe respiratory syncytial virus (RSV) lower respiratory tract infection. Passive immunity is the mainstay of infection prevention in this cohort. Transplacental transfer of maternal antibodies provides the newborn with immediate protection from life-threatening infections, however, is dependent upon gestational age, birth weight, mother's age, recent maternal vaccination, maternal nutritional status, maternal immunocompetence and medical conditions, and placental integrity. Efficient transplacental transfer of RSV-neutralizing antibodies have led to the development and approval of maternal RSV immunization for the protection of the newborn. Additionally, administration of RSV-specific antibodies to infants leads to high serum titers of RSV-neutralizing antibodies and further protection from severe disease.

Characteristics of failure of passive transfer at the herd level using the serum immunoglobulin G concentration as an indicator on dairy farms in eastern Hokkaido, Japan.

The objectives of this study were to conduct a survey of failure-of-passive-transfer (FPT) in eastern Hokkaido Japan, to evaluate the association between herd-level FPT and death and culling or treatment, and to test the effectiveness of monitoring using herd-level FPT. A total of 4,411 Holstein and Holstein-Wagyu crossbreds calves born from Holstein dams during the year beginning April 2, 2019 on 39 dairy farms were included in the study to investigate death-and-culling and the treatment rate during the first month of life, as well as rearing management up to 3 weeks of age. A subset of Holsteins (n=381) was included in the study for passive transfer and farms were diagnosed as having FPT if more than 20% of newborn calves had serum IgG levels below 10 g/L at the herd level. The prevalence of FPT (