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1.
Viruses ; 14(7)2022 Jun 30.
Article in English | MEDLINE | ID: covidwho-1917789

ABSTRACT

COVID-19 convalescent plasma (CCP) has been the only specific anti-viral therapy against SARS-CoV-2 available for more than one year. Following the negative results from most randomized controlled trials on its efficacy in COVID-19 hospitalized patients and the availability of anti-spike monoclonal antibodies (mAbs), the use of CCP has subsequently rapidly faded. However, the continuous appearance of new variants of concern (VOCs), most of which escape mAbs and vaccine-elicited neutralizing antibodies (nAbs), has renewed the interest towards CCP, at least in seronegative immunocompetent patients, and in immunocompromised patients not able to mount a protective immune response. We report here the experience of a single Italian hospital in collecting and transfusing CCP in immunocompromised patients hospitalized for severe COVID-19 between October 2021 and March 2022. During this 6-month period, we collected CCP from 32 vaccinated and convalescent regular blood donors, and infused high nAb-titer CCP units (titered against the specific VOC affecting the recipient) to 21 hospitalized patients with severe COVID-19, all of them seronegative at the time of CCP transfusion. Patients' median age was 66 years (IQR 50-74 years) and approximately half of them (47.6%, 10/21) were immunocompromised. Two patients were rescued after previous failure of mAbs. No adverse reactions following CCP transfusion were recorded. A 28-day mortality rate of 14.3 percent (3/21) was reported, with age, advanced disease stage and late CCP transfusion associated with a worse outcome. This real-life experience also supports the use of CCP in seronegative hospitalized COVID-19 patients during the Delta and Omicron waves.


Subject(s)
COVID-19 , SARS-CoV-2 , Aged , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/therapy , Humans , Immunization, Passive/methods
2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-337642

ABSTRACT

Background Antiviral therapy has a greater impact when provided early in the disease to outpatients, potentially preventing hospitalization and subsequent deaths, while reducing healthcare system pressure. Controversies persist about the best treatment option for COVID-19 outpatients at risk of disease progression to hospital. No head-to-head RCT has been conducted to compare the three major modalities in current use-oral/intravenous antivirals, monoclonal antibodies and COVID-19 convalescent plasma (CCP). Methods We assembled data from March 2020 to April 2022 from published outpatient RCTs examining authorized COVID-19 therapies with hospitalization as the major endpoint, and that also assessed mortality, symptom resolution, underlying risk factors for progression, timing and dose of the intervention in relationship to evolving variants of concern (VOC). Findings CCP, monoclonal antibodies and oral antivirals each had comparable efficacy converging to 80% hospital risk reduction dependent on the dose and the timing of the intervention. Most RCTs targeted populations with at least one risk factor for severe COVID-19. Control group hospitalizations were less than 10% in 16 of 20 RCTs. Amongst the effective two CCP trials, monoclonals and three antiviral small molecules, deaths were reduced by 90% from 44 total in combined control arm to 4 in intervention arms. The overall risk of bias was deemed low for nine studies and some concerns for eight. The I 2 statistic heterogeneity amongst the outpatient trials with endpoint hospitalization is 72% (p-< 0.01). Interpretation The emerging resistance of Omicron BA.2 and related sublineages (XE, BA.2.12.1, BA.4, and BA.5) to monoclonal antibodies suggests a pressing need to reevaluate CCP (nowadays largely available from vaccinees with high neutralizing antibody levels) for COVID19 outpatients at risk of disease progression, especially in settings with constrained medical resources. Funding This study was funded by the US Department of Defense, in collaboration with the Defense Health Agency and NIH. Research in context Evidence before this study To date no head-to-head randomized controlled trial (RCT) has ever compared treatment options for COVID-19 outpatients, making comparisons and treatment choices difficult. We assembled RCTs with hospitalization as the primary endpoint. A literature search of MEDLINE (through PubMed), medRxiv and bioRxiv databases was carried out inclusive of RCTs published from March 2020 to April 2022 inclusive, using the search terms (“COVID-19” OR “SARS-CoV-2” OR “coronavirus disease 2019”) AND (“treatment” OR “therapy”) AND (“outpatient” OR “hospitalization”). The risk of bias obtained at COVID-19-Network Meta-Analysis (NMA), was low in half of the studies with some concerns for the remaining. Added value of this study This systematic review compared outcomes among RCTs of outpatient therapy for COVID-19, taking into account time between onset of symptoms and treatment administration. We found that small-chemical antivirals, convalescent plasma and anti-Spike monoclonal antibodies had comparable efficacy. Trials of monoclonals were performed prior to the recognition that they had become ineffective against the Omicron sublineages. Implications of all the available evidence Monoclonal antibodies and small chemical antivirals each have drawbacks. Both take time to be developed and are expensive. Monoclonals can lose efficacy with viral mutation, and chemical antivirals have contraindications and adverse events. Convalescent plasma retains its potency and is likely to be the only accessible therapeutic option for low-and-middle income countries.

3.
Vox Sang ; 117(5): 641-646, 2022 May.
Article in English | MEDLINE | ID: covidwho-1840539

ABSTRACT

COVID-19 convalescent plasma (CCP) was among the few frontline therapies used to treat COVID-19. After large randomized controlled trials (RCTs) relying on late use in hospitalized patients and/or low antibody titres failed to meet their predefined primary endpoint, the infectious disease community reduced usage of CCP in favour of monoclonal antibodies. Consequently, there are CCP stocks at most transfusion centres worldwide, although scattered usage continues. Further, better designed RCTs are also being launched. The urgent question here is: should we use CCP units collected months before given the largely changed viral variant landscape? We review here in vitro evidence that discourages usage of such CCP units against Delta and other variants of concern. CCP collections should be continued in order to update the armamentarium of therapeutics against vaccine breakthrough infections or in unvaccinated patients and is especially relevant in next-generation RCTs.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , COVID-19/therapy , Humans , Immunization, Passive
4.
Transfusion ; 62(6): 1171-1176, 2022 06.
Article in English | MEDLINE | ID: covidwho-1794552

ABSTRACT

BACKGROUND: Novel SARS-CoV-2 variants of concern (VOC) Delta and Omicron are able to escape some monoclonal antibody therapies, making again COVID-19 convalescent plasma (CCP) a potential frontline treatment. STUDY DESIGN/METHODS: In this study, we investigated the kinetics of anti-SARS-CoV-2 neutralizing antibodies (nAbs) against VOCs Delta and Omicron in vaccine breakthrough infected plasma donors. Serum samples from 19 donors were collected at the time of plasma donation and tested for anti-SARS-CoV-2 nAbs (using live authentic VOC viral neutralization test) and IgG (Liaison® SARS-CoV-2 S1/S2 and Liaison® SARS-CoV-2 TrimericS IgG assays, DiaSorin). Measures were correlated with different variables, including the time between last vaccine dose and CCP donation, and time between SARS-COV-2 infection and CCP donation. RESULTS: nAb titers against VOC Delta and Omicron were directly related to the time interval since last vaccine dose to CCP donation, but inversely related to time since COVID19 breakthrough infection. DISCUSSION: SARS-CoV-2 breakthrough infection in vaccinated in donors boosts nAb titers against VOCs Delta and Omicron, but such titers decay shortly after infection. Therefore, CCP must be collected early after vaccine breakthrough infection.


Subject(s)
COVID-19 , Viral Vaccines , Antibodies, Neutralizing , Antibodies, Viral , Blood Donors , COVID-19/prevention & control , COVID-19/therapy , Humans , Immunization, Passive , Immunoglobulin G , Neutralization Tests , SARS-CoV-2
5.
Life (Basel) ; 12(5)2022 Apr 20.
Article in English | MEDLINE | ID: covidwho-1792608

ABSTRACT

Welcome to the Special Issue of Life entitled "Neutralizing-Antibody-Based Treatments for COVID-19: Achievements and Lessons Learnt for Future Pandemics" [...].

6.
Expert Opin Drug Discov ; 17(6): 531-546, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1774242

ABSTRACT

INTRODUCTION: The ongoing COVID19 pandemic represents an unprecedented opportunity to test the feasibility of monoclonal antibody (mAb) therapies against respiratory viruses. While many hurdles were easily predictable (e.g. time to develop, scalability, and economic sustainability), mAb cocktails (i.e. the combination of two mAbs) were finally deployed in 2021, one year after the beginning of the pandemic. Of them, the REGN-COV-2 cocktail was likely the most successful experience and contributed at saving lives at the time of the wave sustained by the Delta variant of concern (VOC). AREAS COVERED: Herein, the authors review the preclinical and clinical history of the casirivimab + imdevimab cocktail for the treatment of novel coronavirus infection. The authors furthermore provide the reader with their perspectives on this cocktail including its current place in the treatment armamentarium. EXPERT OPINION: Unfortunately, results from clinical trials highlighted a very limited efficacy in inpatients; furthermore, the current evidence with regards to its lack of effectiveness against the current dominant VOC (omicron) suggests a very limited use of these drugs in the future. In the authors' opinion, this story reminds us of the limitations of mAb therapies in pandemic settings, and of the inferiority of monoclonal versus polyclonal antibody-based therapeutics in such scenarios.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Neutralizing , COVID-19/drug therapy , Drug Combinations , Humans
7.
Life (Basel) ; 12(3)2022 Mar 14.
Article in English | MEDLINE | ID: covidwho-1742535

ABSTRACT

In Winter 2020, Italy, and in particular the Lombardy region, was the first country in the Western hemisphere to be hit by the COVID-19 pandemic. Plasma from individuals recovered from COVID-19 (COVID-19 convalescent plasma, CCP) was the first therapeutic tool adopted to counteract the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In this retrospective cohort study, we report the experience of the city hospital of Mantua, Lombardy region, on the compassionate use of CCP in patients hospitalized for severe COVID-19. Between April 2020 and April 2021, 405 consecutive COVID-19 patients received 657 CCP units with a median anti-SARS-CoV-2 neutralizing antibody (nAb) titer of 160 (interquartile range (IQR), 80-320). Their median age was 68 years (IQR, 56-78 years), and 62% were males. At enrollment, 55% of patients had an increased body mass index (BMI), and 25.6% had at least three comorbidities. The 28-day crude mortality rate was 12.6% (51/405). Young age (<68 years), mild disease (admission to low-intensity departments) and early treatment (<7 days from symptoms onset) with high nAb titer (≥320) CCP were found as independently associated with a favorable response to CCP treatment. No safety concerns were recorded, with a rate of CCP-related adverse reactions (all of mild intensity) of 1.3%. In our real-life experience, the first in the western world, early administration of high-titer CCP was a safe and effective treatment for hospitalized COVID-19 patients.

9.
Clin Microbiol Rev ; : e0020021, 2022 Mar 09.
Article in English | MEDLINE | ID: covidwho-1736023

ABSTRACT

Convalescent plasma (CP) recurs as a frontline treatment in epidemics because it is available as soon as there are survivors. The COVID-19 pandemic represented the first large-scale opportunity to shed light on the mechanisms of action, safety, and efficacy of CP using modern evidence-based medicine approaches. Studies ranging from observational case series to randomized controlled trials (RCTs) have reported highly variable efficacy results for COVID-19 CP (CCP), resulting in uncertainty. We analyzed variables associated with efficacy, such as clinical settings, disease severity, CCP SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antibody levels and function, dose, timing of administration (variously defined as time from onset of symptoms, molecular diagnosis, diagnosis of pneumonia, or hospitalization, or by serostatus), outcomes (defined as hospitalization, requirement for ventilation, clinical improvement, or mortality), CCP provenance and time for collection, and criteria for efficacy. The conflicting trial results, along with both recent WHO guidelines discouraging CCP usage and the recent expansion of the FDA emergency use authorization (EUA) to include outpatient use of CCP, create confusion for both clinicians and patients about the appropriate use of CCP. A review of 30 available RCTs demonstrated that signals of efficacy (including reductions in mortality) were more likely if the CCP neutralizing titer was >160 and the time to randomization was less than 9 days. The emergence of the Omicron variant also reminds us of the benefits of polyclonal antibody therapies, especially as a bridge to the development and availability of more specific therapies.

10.
Vaccines (Basel) ; 10(3)2022 Mar 08.
Article in English | MEDLINE | ID: covidwho-1732278

ABSTRACT

During the ongoing COVID-19 pandemic, serology has suffered several manufacturing and budget bottlenecks. Kode technology exposes exogenous antigens on the surface of cells; in the case of red blood cells, modified cells are called kodecytes, making antibody-antigen reactions detectable by the old-fashioned hemagglutination test. In this commentary, we review evidence supporting the utility of SARS-CoV-2 Spike kodecytes for clinical diagnostic purposes and serosurveys in resource-poor settings.

11.
Transfusion ; 62(3): 717-719, 2022 03.
Article in English | MEDLINE | ID: covidwho-1673309
12.
International journal of molecular sciences ; 23(1), 2021.
Article in English | EuropePMC | ID: covidwho-1619211

ABSTRACT

The accelerated SARS-CoV-2 evolution under selective pressure by massive deployment of neutralizing antibody-based therapeutics is a concern with potentially severe implications for public health. We review here reports of documented immune escape after treatment with monoclonal antibodies and COVID-19-convalescent plasma (CCP). While the former is mainly associated with specific single amino acid mutations at residues within the receptor-binding domain (e.g., E484K/Q, Q493R, and S494P), a few cases of immune evasion after CCP were associated with recurrent deletions within the N-terminal domain of the spike protein (e.g., ΔHV69-70, ΔLGVY141-144 and ΔAL243-244). The continuous genomic monitoring of non-responders is needed to better understand immune escape frequencies and the fitness of emerging variants.

13.
Vaccines (Basel) ; 10(1)2022 Jan 09.
Article in English | MEDLINE | ID: covidwho-1614039

ABSTRACT

BACKGROUND: Although several therapeutic strategies have been investigated, the optimal treatment approach for patients with coronavirus disease (COVID-19) remains to be elucidated. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of polyclonal intravenous immunoglobulin (IVIG) therapy in COVID-19. METHODS: A systematic literature search using appropriate medical subject heading (MeSH) terms was performed through Medline (PubMed), EMBASE, SCOPUS, OVID and Cochrane Library electronic databases. The main outcomes considered were mortality and safety of IVIG versus placebo/standard of care. This review was carried out in accordance with Cochrane methodology including the risk bias assessment and grading of the quality of evidence. Measures of treatment effect were mean differences (MD) together with 95% confidence intervals (CIs) for continuous outcome measures and risk ratio (RR) or MD for binary outcomes. Two reviewers independently extracted data from individual studies, and disagreements were resolved by a third reviewer. RESULTS: A total of 2401 COVID-19 patients from 10 studies (four randomized controlled trials (RCT) and six non-randomized controlled trials (non-RCTs)) were included in the analysis. Participants received IVIG or placebo/standard of care. The use of IVIG was not associated with a significantly reduced risk of death (RR 0.50, 95% CIs 0.18-1.36, p = 0.17 for RCTs; RR 0.95, 95% CIs 0.61-1.58, p = 0.94 for non-RCTs; low certainty of evidence). IVIG significantly reduced the length of hospital stay (MD -2.24, 95% CIs -3.20/-1.27; p = 0.00001; low certainty of evidence), although this difference was significant only for studies evaluating moderate COVID-19 patients. No significant difference was observed in the incidence of overall and serious adverse events between IVIG recipients and controls (very low certainty of evidence). CONCLUSIONS: The current evidence from the literature does not support the use of IVIG in COVID-19 patients.

15.
Rev Med Virol ; : e2314, 2021 Dec 03.
Article in English | MEDLINE | ID: covidwho-1549282

ABSTRACT

Viral clearance is likely the best way to assess the efficacy of antibody-based therapies. Although antibodies can mediate a variety of effects that include modulation of inflammation, the demonstration of viral clearance provides an accessible and measurable parameter that can be used to evaluate efficacy and determine dosing. Therefore, it is important to ascertain the ability of monoclonal antibodies and convalescent plasma to effect viral clearance. For COVID-19, which is caused by the respiratory virus SARS-CoV-2, the most common assay to assess viral clearance is via a nasopharyngeal swab (NPS). However, assessment of antibody efficacy by sampling this site may be misleading because it may not be as accessible to serum antibodies as respiratory secretions or circulating blood. Adding to the complexity of assessing the efficacy of administered antibody, particularly in randomised controlled trials (RCTs) that enroled patients at different times after the onset of COVID-19 symptoms, viral clearance may also be mediated by endogenous antibody. In this article we critically review available data on viral clearance in RCTs, matched control studies, case series and case reports of antibody therapies in an attempt to identify variables that contribute to antibody efficacy and suggest optimal strategies for future studies.

17.
Diagnostics (Basel) ; 11(9)2021 Sep 11.
Article in English | MEDLINE | ID: covidwho-1408828

ABSTRACT

Convalescent plasma (CP) from patients recovered from COVID-19 is one of the most studied anti-viral therapies against SARS-COV-2 infection. The aim of this study is to summarize the evidence from the available systematic reviews on the efficacy and safety of CP in COVID-19 through an overview of the published systematic reviews (SRs). A systematic literature search was conducted up to August 2021 in Embase, PubMed, Web of Science, Cochrane and Medrxiv databases to identify systematic reviews focusing on CP use in COVID-19. Two review authors independently evaluated reviews for inclusion, extracted data and assessed quality of evidence using AMSTAR (A Measurement Tool to Assess Reviews) and GRADE tools. The following outcomes were analyzed: mortality, viral clearance, clinical improvement, length of hospital stay, adverse reactions. In addition, where possible, subgroup analyses were performed according to study design (e.g., RCTs vs. non-RCTs), CP neutralizing antibody titer and timing of administration, and disease severity. The methodological quality of included studies was assessed using the checklist for systematic reviews AMSTAR-2 and the GRADE assessment. Overall, 29 SRs met the inclusion criteria based on 53 unique primary studies (17 RCT and 36 non-RCT). Limitations to the methodological quality of reviews most commonly related to absence of a protocol (11/29) and funding sources of primary studies (27/29). Of the 89 analyses on which GRADE judgements were made, effect estimates were judged to be of high/moderate certainty in four analyses, moderate in 38, low in 38, very low in nine. Despite the variability in the certainty of the evidence, mostly related to the risk of bias and inconsistency, the results of this umbrella review highlight a mortality reduction in CP over standard therapy when administered early and at high titer, without increased adverse reactions.

20.
Viruses ; 13(8)2021 08 11.
Article in English | MEDLINE | ID: covidwho-1355048

ABSTRACT

COVID-19 convalescent plasma (CCP) is currently under investigation for both treatment and post-exposure prophylaxis. The active component of CCP mediating improved outcome is commonly reported as specific antibodies, particularly neutralizing antibodies, with clinical efficacy characterized according to the level or antibody affinity. In this review, we highlight the potential role of additional factors in CCP that can be either beneficial (e.g., AT-III, alpha-1 AT, ACE2+ extracellular vesicles) or detrimental (e.g., anti-ADAMTS13, anti-MDA5 or anti-interferon autoantibodies, pro-coagulant extracellular vesicles). Variations in these factors in CCP may contribute to varied outcomes in patients with COVID-19 and undergoing CCP therapy. We advise careful, retrospective investigation of such co-factors in randomized clinical trials that use fresh frozen plasma in control arms. Nevertheless, it might be difficult to establish a causal link between these components and outcome, given that CCP is generally safe and neutralizing antibody effects may predominate.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/therapy , SARS-CoV-2/immunology , Anti-Inflammatory Agents/blood , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , Autoantibodies/blood , Blood Coagulation Factor Inhibitors/blood , Blood Coagulation Factors/analysis , Cross Reactions , Extracellular Vesicles , Humans , Immunization, Passive/adverse effects , Immunologic Factors/blood , Immunosuppressive Agents/blood
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