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).

Value profile for respiratory syncytial virus vaccines and monoclonal antibodies.

Respiratory syncytial virus (RSV) is the predominant cause of acute lower respiratory infection (ALRI) in young children worldwide, yet no licensed RSV vaccine exists to help prevent the millions of illnesses and hospitalizations and tens of thousands of young lives taken each year. Monoclonal antibody (mAb) prophylaxis exists for prevention of RSV in a small subset of very high-risk infants and young children, but the only currently licensed product is impractical, requiring multiple doses and expensive for the low-income settings where the RSV disease burden is greatest. A robust candidate pipeline exists to one day prevent RSV disease in infant and pediatric populations, and it focuses on two promising passive immunization approaches appropriate for low-income contexts: maternal RSV vaccines and long-acting infant mAbs. Licensure of one or more candidates is feasible over the next one to three years and, depending on final product characteristics, current economic models suggest both approaches are likely to be cost-effective. Strong coordination between maternal and child health programs and the Expanded Program on Immunization will be needed for effective, efficient, and equitable delivery of either intervention. This 'Vaccine Value Profile' (VVP) for RSV is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships and multi-lateral organizations, and in collaboration with stakeholders from the WHO headquarters. All contributors have extensive expertise on various elements of the RSV VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Immunization, not vaccination: monoclonal antibodies for infant RSV prevention and the US vaccines for children program.

In the US, RSV imposes significant burdens on infants, households, and the health system. Yet the only licensed immunization is accessible to only certain risk groups comprising 2% of the infant population, leaving the remaining 98% unprotected. An effective immunization for all infants is a significant public health priority. One possible solution is the FDA-approved monoclonal antibody nirsevimab, which recent evidence suggests is safe and effective in preventing RSV in all infants, and which is currently being considered for inclusion in the pediatric immunization schedule and the federal Vaccines for Children (VFC) program. But the question arises whether passive immunization products like nirsevimab ought to be eligible for the VFC, which nominally and traditionally centers on vaccines providing active immunity. Addressing this is urgent because VFC inclusion will be decided on imminently. I argue there are strong policy grounds, i.e., reasons grounded in the ultimate health system goals of maximizing population health or social welfare subject to resource constraints, not to exclude passive immunization from VFC eligibility. Active and passive immunizations both provide adaptive immunity and can therefore produce qualitatively similar effects on risks of infection, disease, and transmission; on disease severity and duration; and on health, welfare, and health resource use. The distinction between active and passive immunization does not intrinsically matter since what matters for the attainment of health system goals is the extent of immunity conferred, not whether immunity is active or passive. Nor can passivity be considered a useful proxy for conferring a lesser extent of immunity, since no such proxy is needed (existing valuation methods can cope with variations in product attributes), and it is a poor proxy (passive immunizations can be better for individuals with impaired immune systems and can have comparable effectiveness durations and economic value as vaccines).

Formulation Studies to Develop Low-Cost, Orally-Delivered Secretory IgA Monoclonal Antibodies for Passive Immunization Against Enterotoxigenic Escherichia coli.

Enterotoxigenic Escherichia coli (ETEC) is a common cause for diarrheal infections in children in low- and middle-income countries (LMICs). To date, no ETEC vaccine candidates have been approved. Passive immunization with low-cost, oral formulations of secretory IgA (sIgA) against ETEC is an alternative approach to protect high-risk populations in LMICs. Using a model sIgA monoclonal antibody (anti-LT sIgA2-mAb), the stability profiles of different formulations were assessed during storage and in in vitro digestion models (mimicking in vivo oral delivery). First, by employing various physicochemical techniques and a LT-antigen binding assay, three formulations with varying acid-neutralizing capacity (ANC) were evaluated to stabilize sIgA2-mAb during stress studies (freeze-thaw, agitation, elevated temperature) and during exposure to gastric phase digestion. Next, a low-volume, in vitro intestinal digestion model was developed to screen various additives to stabilize sIgA2-mAb in the intestinal phase. Finally, combinations of high ANC buffers and decoy proteins were assessed to collectively protect sIgA2-mAb during in vitro sequential (stomach to intestine) digestion. Based on the results, we demonstrate the feasibility of low-cost, 'single-vial', liquid formulations of sIgA-mAbs delivered orally after infant feeding for passive immunization, and we suggest future work based on a combination of in vitro and in vivo stability considerations.

Assessment of the impact of pathogen reduction technologies on the neutralizing activity of COVID-19 convalescent plasma.

COVID-19 convalescent plasma (CCP) could improve the clinical outcome of COVID-19 patients when high-titer CCP is administered in early stages of disease. However, CCP donors have a risk profile like first-time donors, pathogen reduction treatment (PRT) may mitigate such risk but should not impact CCP quality. The current study aims to assess the impact of PRT-technologies available in Saudi Arabia on the neutralizing activity of CCP. STUDY DESIGN: and Methods: CCP was collected from eligible donors by plasmapheresis. The neutralization titer was determined with an in-house microneutralization assay (MNA) using a local SARS-CoV-2 clinical isolate. Selected units were split and subject to PRT with amotosalen/UVA (AS) or Riboflavin/UVB (RB) (pairwise side-by-side comparison) followed by a second MNA analysis. 51 CCP units were collected, 27 were included in the analysis reaching the minimum MNA titer of 1:40 (4 reached high titer (≥1:250)). 27 CCP units were treated with AS and 14 with RB, the median MNA pre-treatment titer was 1:80 (1:40-640). The impact of AS and RB PRT on CCP neutralizing activity was not significantly different, nor in the total analysis neither in the pairwise comparison (94.6 vs 96.4 % retention, p > 0.05). No correlation of titer and blood group was observed, but a trend for increasing MNA titer with donor age, choosing donors with an age > 45 years would increase the number of high-titer CCP donors. The difference in impact of AS and RB on CCP MNA titer was below the limit of detection of the assay (0.5-fold).

Early and out-of-hospital use of COVID-19 convalescent plasma: An international assessment of utilization and feasibility.

BACKGROUND AND OBJECTIVES: The use of coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) in the treatment of patients with severe acute respiratory syndrome-2 infection has been controversial. Early administration of CCP before hospital admission offers a potential advantage. This manuscript summarizes current trials of early use of CCP and explores the feasibility of this approach in different countries. MATERIALS AND METHODS: A questionnaire was distributed to the International Society of Blood Transfusion (ISBT) CCP working group. We recorded respondents' input on existing trials on early/outpatient CCP and out-of-hospital (OOH)/home transfusion (HT) practices in their countries and feedback on challenges in initiating home CCP infusion programmes. In addition, details of existing trials registered on clinicaltrials.gov were summarized. RESULTS: A total of 31 country representatives participated. Early/OOH CCP transfusion studies were reported in the United States, the Netherlands, Spain and Brazil. There were a total of six published and five ongoing trials on the prophylactic and therapeutic early use of CCP. HT was practised in Australia, the UK, Belgium, France, Japan, Nigeria, the Netherlands, Spain, Italy, Norway, the United States and some provinces in Canada. Thirty-four representatives indicated a lack of OOH CCP or HT in their institutions and countries. Barriers to implementation of OOH/HT included existing legislation, lack of policies pertaining to outpatient transfusion, and associated logistical challenges, including lack of staffing and resources. CONCLUSION: Early administration of CCP remains a potential option in COVID-19 management in countries with existing OOH/HT programmes. Legislation and regulatory bodies should consider OOH/HT practice for transfusion in future pandemics.

A Rapid and Sensitive Microfluidics-Based Tool for Seroprevalence Immunity Assessment of COVID-19 and Vaccination-Induced Humoral Antibody Response at the Point of Care.

As of 8 August 2022, SARS-CoV-2, the causative agent of COVID-19, has infected over 585 million people and resulted in more than 6.42 million deaths worldwide. While approved SARS-CoV-2 spike (S) protein-based vaccines induce robust seroconversion in most individuals, dramatically reducing disease severity and the risk of hospitalization, poorer responses are observed in aged, immunocompromised individuals and patients with certain pre-existing health conditions. Further, it is difficult to predict the protection conferred through vaccination or previous infection against new viral variants of concern (VoC) as they emerge. In this context, a rapid quantitative point-of-care (POC) serological assay able to quantify circulating anti-SARS-CoV-2 antibodies would allow clinicians to make informed decisions on the timing of booster shots, permit researchers to measure the level of cross-reactive antibody against new VoC in a previously immunized and/or infected individual, and help assess appropriate convalescent plasma donors, among other applications. Utilizing a lab-on-a-chip ecosystem, we present proof of concept, optimization, and validation of a POC strategy to quantitate COVID-19 humoral protection. This platform covers the entire diagnostic timeline of the disease, seroconversion, and vaccination response spanning multiple doses of immunization in a single POC test. Our results demonstrate that this platform is rapid (~15 min) and quantitative for SARS-CoV-2-specific IgG detection.

Manejo clínico y diagnóstico para pacientes con enfermedades de inmunodeficiencia primaria por déficit de producción de anticuerpos / Clinical management and diagnosis for patients with primary immunodeficiency diseases due to deficiency of antibody production

1. INTRODUCCIÓNLas inmunodeficiencias primarias son un grupo de más de 400 enfermedades, en las cuales el sistema inmune pierde sus funciones de reconocimiento de patógenos o funciona de forma inapropiada. Algunas de ellas son relativamente comunes; mientras otras son raras. Estas enfermedades son en ocasiones de por vida, debilitantes y costosas1,2.Sin embargo, muchos progresos se han hecho desde su des-cripción original en el año de 1952. Se han dado grandes pasos en cuanto a su entendimiento de las Inmunodeficiencias Pri-marias a nivel genético, de sus características, y tratamiento. Algunos tipos afectan un único tipo de célula; otros afectan más de un componente del sistema inmune2,3.Tomando en cuenta que la aproximación es entre 1-2% de la población, a nivel país se puede decir que un aproximado entre 170 000 a 340 000 pacientes en el país no cuentan con un diagnóstico y muchos mueren por falta de este. El número de afiliados al Instituto Ecuatoriano de Seguridad Social hasta julio de 2021 es de 3 672,611 por lo que se considera que un estimado de 36 726 a 73 452 pacientes podrían presentar este tipo de enfermedades y requerir de atención por infecciones a repetición, enfermedad autoinmune y enfermedades linfopro-liferativas, además de que sin un tratamiento específico po-drían fallecer debido a infecciones graves o tener discapacidad permanente, lo que implica mayor carga para el sistema de Seguridad Social en subsidios y menores ingresos. Ecuador, cuenta con 86 pacientes diagnosticados, según la base de datos de la Sociedad Latino-Americana de Inmunodeficiencias4.Algunas terapias, como la de reemplazo para inmunoglobu-linas, a la que es tributaria más del 60% de estas patologías permite que la esperanza de vida y la morbilidad casi alcancen a aquellos que no presentan la enfermedad5­7.

1. INTRODUCTIONPrimary immunodeficiencies are a group of more than 400 diseases, in which the immune system loses its pathogen recog-nition functions or functions inappropriately. Some of them are relatively common, while others are rare. These diseases are sometimes lifelong, debilitating, and costly1,2. However, much progress has been made since its original description in 1952. Great strides have been made in understanding Primary Immunodeficiencies at the genetic level, their characteristics, and treatment. Some types affect only one type of cell; others affect more than one component of the immune system2,3. Considering that the approximation is between 1 to 2% of the population, at the country level we could say that approximately between 170 000 to 340 000 patients in the country do not have a diagnosis and many die due to lack of it. The number of social security affiliates until July 2021 is 3 672,611, so we could consider that approximately 36 726 to 73 452 patients could present this type of disease and require care for recurrent infections, autoimmune disease and lymphoproliferative diseases, in addition to the fact that without specific treatment they could die due to serious infections or have permanent disability, which implies a greater burden for the social security system in subsidies and lower income. Currently the country has 86 diagnosed patients, according to the database of the Latin American Society of Immunodeficiencies4. Many of the therapies, such as immunoglobulin replacement therapy, to which more than 60% of these pathologies are de-pendent, allow life expectancy and morbidity to almost reach those who do not have the disease 5­7.

Development of a cost-effective ovine antibody-based therapy against SARS-CoV-2 infection and contribution of antibodies specific to the spike subunit proteins.

Antibodies against SARS-CoV-2 are important to generate protective immunity, with convalescent plasma one of the first therapies approved. An alternative source of polyclonal antibodies suitable for upscaling would be more amendable to regulatory approval and widespread use. In this study, sheep were immunised with SARS-CoV-2 whole spike protein or one of the subunit proteins: S1 and S2. Once substantial antibody titres were generated, plasma was collected and samples pooled for each antigen. Non-specific antibodies were removed via affinity-purification to yield candidate products for testing in a hamster model of SARS-CoV-2 infection. Affinity-purified polyclonal antibodies to whole spike, S1 and S2 proteins were evaluated for in vitro for neutralising activity against SARS-CoV-2 Wuhan-like virus (Australia/VIC01/2020) and a recent variant of concern, B.1.1.529 BA.1 (Omicron), antibody-binding, complement fixation and phagocytosis assays were also performed. All antibody preparations demonstrated an effect against SARS-CoV-2 disease in the hamster model of challenge, with those raised against the S2 subunit providing the most promise. A rapid, cost-effective therapy for COVID-19 was developed which provides a source of highly active immunoglobulin specific to SARS-CoV-2 with multi-functional activity.

Development and implementation of a COVID-19 convalescent plasma program in a middle-income economy

Abstract Introduction Convalescent Plasma therapy is one of the therapeutic strategies that has been used for patients with the Covid-19 disease. Implementing a program with national extension to supply hospitals with this blood component is a great challenge mainly in a middle-income economy. Objectives Our objective was to develop and implement a Covid-19 Convalescent Plasma Program which met established quality standards and was adapted to a reality of limited resources. Methods A multicentric convalescent plasma collection program was developed and implemented, based on four main sequential procedures: selective donor recruitment, pre-donation antibody screening (Anti-SARS-CoV-2- Chemiluminescence IgG Abbott), convalescent plasma collection by apheresis or whole-blood processing and distribution to the hospitals according to local demand. Results From the 572 candidates submitted to the pre-donation antibody screening, only 270 (47%) were considered eligible for plasma donation according to the established criteria. Higher levels of total antibody were associated with the donor age being above 45 years old (p= 0.002), hospital admission (p= 0.018), and a shorter interval between the diagnosis of the SARS-CoV-2 infection and plasma donation (p < 0.001). There was no association between the ABO and Rh blood groups and their antibody levels. Of the 468 donations made, 61% were from the collection of whole-blood and 39%, from apheresis. The Covid-19 Convalescent Plasma units obtained were distributed to 21 different cities throughout the country by air or ground transportation. Conclusion The implementation of a Covid-19 Convalescent Plasma program in a continental country with relatively scarce resources is feasible with alternative strategies to promote lower cost procedures, while complying with local regulations and meeting quality standards.

Uso de plasma convalescente no tratamento da COVID-19: protocolo de revisão sistemática / Use of convalescent plasma in the treatment of COVID-19: a systematic review protocol / Uso de plasma convaleciente en el tratamiento de COVID-19: protocolo de revisión sistemática

OBJETIVO: analisar a efetividade terapêutica do plasma convalescente utilizado em pacientes com confirmação de diagnóstico de COVID-19. MÉTODO: revisão sistemática para avaliação tecnológica em saúde para responder à pergunta PICO: O plasma convalescente é efetivo na redução da carga viral de pacientes com diagnóstico SARS-CoV-2 (COVID-19) quando comparado ao não uso do plasma? Foi realizada uma busca sistemática nas bases de dados Pubmed/Medline, BVS, Embase, CINAHL, LILACS, Cochrane e Google Scholar. A triagem inicial dos títulos e resumos será avaliada de forma independente por dois revisores. Para avaliação do risco de viés de revisões sistemáticas será utilizado o AMSTAR-2; já para avaliação da qualidade da evidência será aplicado o GRADE.

OBJECTIVE: to analyze the therapeutic effectiveness of convalescent plasma used in patients with confirmed COVID-19 diagnosis. METHOD: systematic review for health technology assessment to answer the PICO question: Is convalescent plasma effective in reducing the viral load of patients diagnosed with SARS-CoV-2 (COVID-19) when compared to not using plasma? A systematic search was performed in Pubmed/Medline, BVS, Embase, CINAHL, LILACS, Cochrane and Google Scholar databases. The initial screening of titles and abstracts will be independently assessed by two reviewers. To assess the risk of bias in systematic reviews, AMSTAR-2 will be used,and to assess the quality of evidence, GRADE will be used.

OBJETIVO: analizar la efectividad terapéutica del plasma convaleciente utilizado en pacientes con confirmación de diagnóstico de COVID-19. MÉTODO: revisión sistemática para evaluación tecnológica en salud para responder a la pregunta PICO ¿Es el plasma convaleciente efetivo en la reducción de la carga viral de pacientes con diagnóstico SARS-CoV-2(COVID-19) cuando se la compara a la no utilización del plasma Se realizó una búsqueda sistemática en las bases de datos Pubmed/Medline, BVS, Embase, CINAHL,L ILACS, Cochrane y Google Scholar. La selección inicial de los títulos y resúmenes serán evaluados de forma independiente por dos revisores. Para evaluación del riesgo de sesgo de revisiones sistemáticas se utilizará el AMSTAR-2, mas para evaluación de la calidad de la evidencia será aplicado el GRADE.

Assessment of anti-SARS-CoV-2 antibodies level in convalescents plasma.

Despite extensive vaccination, the quantity of patients infected with the SARS-CoV-2 virus and its variants continues to grow worldwide. Treating patients with a severe course of COVID-19 is a difficult challenge. One of the generally accepted and specific therapy methods is the use of plasma rich in anti-SARS-CoV-2 antibodies. On the other hand, assessing the antibodies level depending on the time after infection allows for vaccine-decision. The study marked the level of anti-SARS-CoV-2 IgG antibodies in 351 COVID-19 convalescent residents of one geographical region in Poland. The study group included blood donors. The studies were cross-sectional and extended to a questionnaire to determine infection severity. These data were compiled statistically. The study considered epidemiological factors, the time from the end of the infection, and infection severity. The fastest increase of the antibodies level was observed up to 59 days after COVID-19, and it was statistically significantly higher among men. Higher levels of antibodies were found among people above the average age in both men and women. There was an increase in the level of antibodies since the onset of the disease in men, while in women, it decreased. The antibodies level was also found to depend on the severity of the course of COVID-19 infection. The optimal group of plasma donors in the studied geographical region is men and women above 39 years old. after a more severe infection. The titer of antibodies increases with time from the disease.

Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study.

BACKGROUND: The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. METHODS AND FINDINGS: Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician-principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had-or were at risk of progression to-severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects. CONCLUSIONS: These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT#: NCT04338360.

Anti-SARS-CoV-2 Strategies and the Potential Role of miRNA in the Assessment of COVID-19 Morbidity, Recurrence, and Therapy.

Recently, we have experienced a serious pandemic. Despite significant technological advances in molecular technologies, it is very challenging to slow down the infection spread. It appeared that due to globalization, SARS-CoV-2 spread easily and adapted to new environments or geographical or weather zones. Additionally, new variants are emerging that show different infection potential and clinical outcomes. On the other hand, we have some experience with other pandemics and some solutions in virus elimination that could be adapted. This is of high importance since, as the latest reports demonstrate, vaccine technology might not follow the new, mutated virus outbreaks. Thus, identification of novel strategies and markers or diagnostic methods is highly necessary. For this reason, we present some of the latest views on SARS-CoV-2/COVID-19 therapeutic strategies and raise a solution based on miRNA. We believe that in the face of the rapidly increasing global situation and based on analogical studies of other viruses, the possibility of using the biological potential of miRNA technology is very promising. It could be used as a promising diagnostic and prognostic factor, as well as a therapeutic target and tool.

Assessment of serological assays for identifying high titer convalescent plasma.

BACKGROUND: The COVID-19 pandemic has been accompanied by the largest mobilization of therapeutic convalescent plasma (CCP) in over a century. Initial identification of high titer units was based on dose-response data using the Ortho VITROS IgG assay. The proliferation of severe acute respiratory syndrome coronavirus 2 serological assays and non-uniform application has led to uncertainty about their interrelationships. The purpose of this study was to establish correlations and analogous cutoffs between multiple serological assays. METHODS: We compared the Ortho, Abbott, Roche, an anti-spike (S) ELISA, and a virus neutralization assay. Relationships relative to FDA-approved cutoffs under the CCP emergency use authorization were identified in convalescent plasma from a cohort of 79 donors from April 2020. RESULTS: Relative to the neutralization assay, the spearman r value of the Ortho Clinical, Abbott, Roche, anti-S ELISA assays was 0.65, 0.59, 0.45, and 0.76, respectively. The best correlative index for establishing high-titer units was 3.87 signal-to-cutoff (S/C) for the Abbott, 13.82 cutoff index for the Roche, 1:1412 for the anti-S ELISA, 1:219 by the neutralization assay, and 15.9 S/C by the Ortho Clinical assay. The overall agreement using derived cutoffs compared to a neutralizing titer of 1:250 was 78.5% for Abbott, 74.7% for Roche, 83.5% for the anti-S ELISA, and 78.5% for Ortho Clinical. DISCUSSION: Assays based on antibodies against the nucleoprotein were positively associated with neutralizing titers and the Ortho assay, although their ability to distinguish FDA high-titer specimens was imperfect. The resulting relationships help reconcile results from the large body of serological data generated during the COVID-19 pandemic.

Scalable, Micro-Neutralization Assay for Assessment of SARS-CoV-2 (COVID-19) Virus-Neutralizing Antibodies in Human Clinical Samples.

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic expanded, it was clear that effective testing for the presence of neutralizing antibodies in the blood of convalescent patients would be critical for development of plasma-based therapeutic approaches. To address the need for a high-quality neutralization assay against SARS-CoV-2, a previously established fluorescence reduction neutralization assay (FRNA) against Middle East respiratory syndrome coronavirus (MERS-CoV) was modified and optimized. The SARS-CoV-2 FRNA provides a quantitative assessment of a large number of infected cells through use of a high-content imaging system. Because of this approach, and the fact that it does not involve subjective interpretation, this assay is more efficient and more accurate than other neutralization assays. In addition, the ability to set robust acceptance criteria for individual plates and specific test wells provided further rigor to this assay. Such agile adaptability avails use with multiple virus variants. By February 2021, the SARS-CoV-2 FRNA had been used to screen over 5000 samples, including acute and convalescent plasma or serum samples and therapeutic antibody treatments, for SARS-CoV-2 neutralizing titers.

Respiratory syncytial virus seasonality and prevention strategy planning for passive immunisation of infants in low-income and middle-income countries: a modelling study.

BACKGROUND: Respiratory syncytial virus (RSV) represents a substantial burden of disease in young infants in low-income and middle-income countries (LMICs). Because RSV passive immunisations, including maternal vaccination and monoclonal antibodies, can only grant a temporary period of protection, their effectiveness and efficiency will be determined by the timing of the immunisation relative to the underlying RSV seasonality. We aimed to assess the potential effect of different approaches for passive RSV immunisation of infants in LMICs. METHODS: We included 52 LMICs in this study on the basis of the availability of RSV seasonality data and developed a mathematical model to compare the effect of different RSV passive immunisation approaches (seasonal approaches vs a year-round approach). For each candidate approach, we calculated the expected annual proportion of RSV incidence among infants younger than 6 months averted (effectiveness) and the ratio of per-dose cases averted between that approach and the year-round approach (relative efficiency). FINDINGS: 39 (75%) of 52 LMICs included in the study had clear RSV seasonality, defined as having more than 75% of annual RSV cases occurring in 5 or fewer months. In these countries with clear RSV seasonality, the seasonal approach in which monoclonal antibody administration began 3 months before RSV season onset was only a median of 16% (IQR 13-18) less effective in averting RSV-associated acute lower respiratory infection (ALRI) hospital admissions than a year-round approach, but was a median of 70% (50-97) more efficient in reducing RSV-associated hospital admissions per dose. The seasonal approach that delivered maternal vaccination 1 month before the season onset was a median of 27% (25-33) less effective in averting hospital admissions associated with RSV-ALRI than a year-round approach, but was a median of 126% (87-177) more efficient at averting these hospital admissions per dose. INTERPRETATION: In LMICs with clear RSV seasonality, seasonal approaches to monoclonal antibody and maternal vaccine administration might optimise disease prevention by dose given compared with year-round administration. More data are needed to clarify if seasonal administration of RSV monoclonal antibodies or maternal immunisation is programmatically suitable and cost effective in LMICs. FUNDING: The Bill & Melinda Gates Foundation, World Health Organization.

Preparedness and activities of the anti-SARS-CoV-2 convalescent plasma bank in the Veneto region (Italy): An organizational model for future emergencies.

BACKGROUND: Convalescent plasma (CP) has been used in the past in various pandemics, in particular in H1N1, SARS and MERS infections. In Spring 2020, when ongoing the SARS-CoV-2 pandemics, the Veneto Region (V-R) has proposed setting-up an anti-SARS-CoV-2 CP (CCP) Bank, with the aim of preparing a supply of CCP immediately available in case of subsequest epidemic waves. MATERIALS AND METHODS: Key-points to be developed for a quick set-up of the V-R CCP Bank have been recruitment of donors recovered from COVID-19 infection, laboratory analysis for the biological qualification of the CCP units, including titre of neutralizing antibodies and reduction of pathogens, according to National Blood Centre (CNS) Directives, adaptation of the V-R Information Technology systems and cost analysis. Some activities, including diagnostic and viral inactivation processes, have been centralized in 2 or 3 sites. Laboratory analysis upon preliminary admission of the donor included all tests required by the Italian laws and the CNS directives. RESULTS: From April to August 2020, 3,298 people have contacted the V-R Blood Transfusion Services: of these, 1,632 have been evaluated and examined as first time donors and those found to be suitable have carried out 955 donations, from which 2,626 therapeutic fractions have been obtained, at a cost around 215,00 Euro. Since October 2020, the number of COVID-19 inpatients has had a surge with a heavy hospital overload. Moreover, the high request of CCP therapy by clinicians has been just as unexpected, showing a wide therapeutic use. CONCLUSIONS: The organizational model here presented, which has allowed the rapid collection of a large amount of CCP, could be useful when facing new pandemic outbreaks, especially in low and middle income countries, with generally acceptable costs.