Monoclonal antibody therapies against SARS-CoV-2.

Monoclonal antibodies (mAbs) targeting the spike protein of SARS-CoV-2 have been widely used in the ongoing COVID-19 pandemic. In this paper, we review the properties of mAbs and their effect as therapeutics in the pandemic, including structural classification, outcomes in clinical trials that led to the authorisation of mAbs, and baseline and treatment-emergent immune escape. We show how the omicron (B.1.1.529) variant of concern has reset treatment strategies so far, discuss future developments that could lead to improved outcomes, and report the intrinsic limitations of using mAbs as therapeutic agents.

Cases of acquired hemophilia A following COVID-19 vaccines: Cogent safety signal or possible reporting/detection bias? Preliminary evidence from Tuscany, Italy.

PURPOSE: Several case reports of acquired hemophilia A (AHA) following COVID-19 vaccines were recently published. A possible increased incidence of AHA during the COVID-19 vaccination campaign was also suggested. We aimed at generating evidence for the preliminary assessment of the association between AHA and COVID-19 vaccination through an ecological study in one Italian region, Tuscany. METHODS: An ecological study was performed using the population-based administrative data source of Tuscany. Per each year between 2017 and 2021, we included patients aged 5+ and active into the database as of January 1. Temporal patterns of annual incidence of possible AHA cases and AHA-tested patients were respectively observed. The rates of possible AHA cases per AHA-tested patients were calculated in 2021 and 2017-2019, respectively (calendar year 2020 was excluded because non-representative of the pre-pandemic era). Age-sex standardization was applied. Poisson's 95% confidence intervals (95% CI) were estimated. Statically significant differences were defined as absence of 95% CI overlap. RESULTS: In 2021, standardized incidence of both possible AHA cases (5.6/million subjects/year; 95% CI = 3.4-8.7) and AHA-tested patients (60.7/1000 subjects/year; 95% CI = 60.4-60.9) showed the lowest point estimates, though only the latter was statistically different compared to previous calendar years. The standardized rate of possible AHA cases per AHA-tested patients was 9.2/100000 (95% CI = 5.6-14.3) in 2021 and 12.5/100000 (95% CI = 8.2-18.1) during 2017-2019. CONCLUSIONS: These preliminary findings do not support the hypothesis of an increased incidence of AHA cases during the COVID-19 vaccination campaign. However, in 2021, the still ongoing healthcare access restrictions might have contributed to the low incidence of AHA and laboratory tests observed. Therefore, large-scale multi-database studies are warranted.

Investigating a Signal of Acquired Hemophilia Associated with COVID-19 Vaccination: A Systematic Case Review.

Acquired hemophilia A (AHA), a rare but life-threatening disorder, most commonly occurs in older people and during pregnancy. During the coronavirus disease 2019 (COVID-19) vaccination campaign, an unexpected number of newly diagnosed AHA patients have been identified in clinical practice that were temporally related to COVID-19 vaccination. We present the result of a signal detection analysis aimed at exploring a possible association between COVID-19 immunization and occurrence of AHA. A disproportionality analysis on the World Health Organization (WHO) database was performed to investigate the presence of a signal of risk for AHA associated with COVID-19 vaccines. Reports of AHA associated with any COVID-19 vaccine included in the WHO database were then integrated with those available on the Food and Drug Administration Vaccine Adverse Events Reporting System and those published in the medical literature. The WHO database included 146 reports of AHA. The information component (IC) was significant for the association of AHA with all COVID-19 vaccines (IC025: 1.1) and with the vaccine product BNT162b2 (IC025: 1.6). After duplicate exclusion, 96 unique cases of AHA following COVID-19 vaccines have been reviewed. Median time to diagnosis was 18 days and 40% of cases documented the occurrence after the second dose. Overall, in 57% of the investigated cases, a preexisting condition predisposing to AHA was excluded. About 22% of cases occurred in subjects with age ≤65 years and there was no case associated with pregnancy. Mortality was 11%. Although we cannot exclude that the unexpected frequency of AHA diagnosis can be explained by a detection bias, the signal for COVID-19 vaccine-related AHA is robust and deserves further investigations.

Tixagevimab + cilgavimab against SARS-CoV-2: the preclinical and clinical development and real-world evidence.

INTRODUCTION: Direct-acting SARS-CoV-2 antiviral monoclonal antibodies have been an integral part of therapeutic strategies against COVID-19 pandemic. The monoclonal strategy was jeopardized by the emergence of new variants and resistant strains, making many monoclonal antibodies quickly obsolete. Nevertheless, a possible strategy consists in the use of antibody cocktails and the development of the cilgavimab + tixagevimab in combination is placed in this context. AREAS COVERED: In this review, we describe the development of the cilgavimab + tixagevimab cocktail, from pre-clinical to real-world evidence. EXPERT OPINION: The pre-clinical and clinical development of cilgavimab + tixagevimab followed a similar path to that of the antibodies developed in the earlier stages of the pandemic. Both antibodies have been developed from convalescent plasma and have been shown to be effective in clinical trials in prophylaxis and in early therapy. This cocktail has found its position in therapy especially in immunocompromised subjects for whom vaccine prevention is not feasible. The cocktail strategy, together with a more stable pandemic situation, could ensure a certain longevity to the drug against resistance, especially when compared with that of other antibodies. Recently emerged Omicron sub-lineages have demonstrated the ability to escape this cocktail's activity and so the future of this treatment could be compromised.

Prescription of Anti-Spike Monoclonal Antibodies in COVID-19 Patients with Resistant SARS-CoV-2 Variants in Italy.

Anti-Spike monoclonal antibodies have been considered a promising approach to COVID-19 therapy. Unfortunately, the advent of resistant lineages jeopardized their effectiveness and prompted limitations in their clinical use. Change in the dominant variant can be fast to such an extent that, in the absence of timely medical education, prescribers can keep using these drugs for relatively long periods even in patients with resistant variants. Therefore, many patients could have been exposed to drugs with unlikely benefits and probable risks. We show here that about 20% of bamlanivimab+etesevimab, 30% of casirivimab+imdevimab, and 30% of sotrovimab courses were administered in Italy during periods in which a fully resistant variant was dominant. Additionally, for monoclonal antibody cocktails, the vast majority of usage occurred against variants for which one of the mAbs within the cocktail was ineffective. Given the high costs of these drugs and their potential side effects, it would be important to consider a frequent review of the appropriateness of these drugs and timely communication when the benefit/risk balance is no longer favorable.

Preclinical discovery and development of the casirivimab + imdevimab cocktail for the treatment of novel coronavirus infection: the rise and fall.

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.

Efficacy of High-Dose Polyclonal Intravenous Immunoglobulin in COVID-19: A Systematic Review.

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.

COVID-19 Vaccination in Pregnancy, Paediatrics, Immunocompromised Patients, and Persons with History of Allergy or Prior SARS-CoV-2 Infection: Overview of Current Recommendations and Pre- and Post-Marketing Evidence for Vaccine Efficacy and Safety.

To date, four vaccines have been authorised for emergency use and under conditional approval by the European Medicines Agency to prevent COVID-19: Comirnaty, COVID-19 Vaccine Janssen, Spikevax (previously COVID-19 Vaccine Moderna) and Vaxzevria (previously COVID-19 Vaccine AstraZeneca). Although the benefit-risk profile of these vaccines was proven to be largely favourable in the general population, evidence in special cohorts initially excluded from the pivotal trials, such as pregnant and breastfeeding women, children/adolescents, immunocompromised people and persons with a history of allergy or previous SARS-CoV-2 infection, is still limited. In this narrative review, we critically overview pre- and post-marketing evidence on the potential benefits and risks of marketed COVID-19 vaccines in the above-mentioned special cohorts. In addition, we summarise the recommendations of the scientific societies and regulatory agencies about COVID-19 primary prevention in the same vaccinee categories.

The Impact of the COVID-19 "Infodemic" on Drug-Utilization Behaviors: Implications for Pharmacovigilance.

The coronavirus disease 2019 (COVID-19) pandemic that hit the world in 2020 triggered a massive dissemination of information (an "infodemic") about the disease that was channeled through the print, broadcast, web, and social media. This infodemic also included sensational and distorted information about drugs that likely first influenced opinion leaders and people particularly active on social media and then other people, thus affecting choices by individual patients everywhere. In particular, information has spread about some drugs approved for other indications (chloroquine, hydroxychloroquine, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, favipiravir, and umifenovir) that could have led to inappropriate and therefore hazardous use. In this article, we analyze the rationale behind the claims for use of these drugs in COVID-19, the communication about their effects on the disease, the consequences of this communication on people's behavior, and the responses of some influential regulatory authorities in an attempt to minimize the actual or potential risks arising from this behavior. Finally, we discuss the role of pharmacovigilance stakeholders in emergency management and possible strategies to deal with other similar crises in the future.

Large-Scale Postmarketing Surveillance of Biological Drugs for Immune-Mediated Inflammatory Diseases Through an Italian Distributed Multi-Database Healthcare Network: The VALORE Project.

BACKGROUND: Biological drugs have improved the management of immune-mediated inflammatory diseases (IMIDs) despite being associated with important safety issues such as immunogenicity, infections, and malignancies in real-world settings. OBJECTIVE: The aim of this study was to explore the potential of a large Italian multi-database distributed network for use in the postmarketing surveillance of biological drugs, including biosimilars, in patients with IMID. METHODS: A retrospective cohort study was conducted using 13 Italian regional claims databases during 2010-2019. A tailor-made R-based tool developed for distributed analysis of claims data using a study-specific common data model was customized for this study. We measured the yearly prevalence of biological drug users and the frequency of switches between originator and biosimilars for infliximab, etanercept, and adalimumab separately and stratified them by calendar year and region. We then calculated the cumulative number of users and person-years (PYs) of exposure to individual biological drugs approved for IMIDs. For a number of safety outcomes (e.g., severe acute respiratory syndrome coronavirus 2 [SARS-COV-2] infection), we conducted a sample power calculation to estimate the PYs of exposure required to investigate their association with individual biological drugs approved for IMIDs, considering different strengths of association. RESULTS: From a total underlying population of almost 50 million inhabitants from 13 Italian regions, we identified 143,602 (0.3%) biological drug users, with a cumulative exposure of 507,745 PYs during the entire follow-up. The mean age ± standard deviation of biological drug users was 49.3 ± 16.3, with a female-to-male ratio of 1.2. The age-adjusted yearly prevalence of biological drug users increased threefold from 0.7 per 1000 in 2010 to 2.1 per 1000 in 2019. Overall, we identified 40,996 users of biosimilars of tumor necrosis factor (TNF)-α inhibitors (i.e., etanercept, adalimumab, and infliximab) in the years 2015-2019. Of these, 46% (N = 18,845) switched at any time between originator and biosimilars or vice versa. To investigate a moderate association (incidence rate ratio 2) between biological drugs approved for IMIDs and safety events of interest, such as optic neuritis (lowest background incidence rate 10.4/100,000 PYs) or severe infection (highest background incidence rate 4312/100,000 PYs), a total of 43,311 PYs and 104 PYs of exposure to individual biological drugs, respectively, would be required. As such, using this network, of 15 individual biological drugs approved for IMIDs, the association with those adverse events could be investigated for four (27%) and 14 (93%), respectively. CONCLUSION: The VALORE project multi-database network has access to data on more than 140,000 biological drug users (and > 0.5 million PYs) from 13 Italian regions during the years 2010-2019, which will be further expanded with the inclusion of data from other regions and more recent calendar years. Overall, the cumulated amount of person-time of exposure to biological drugs approved for IMIDs provides enough statistical power to investigate weak/moderate associations of almost all individual compounds and the most relevant safety outcomes. Moreover, this network may offer the opportunity to investigate the interchangeability of originator and biosimilars of several TNFα inhibitors in different therapeutic areas in real-world settings.

An overview of the preclinical discovery and development of bamlanivimab for the treatment of novel coronavirus infection (COVID-19): reasons for limited clinical use and lessons for the future.

Introduction: In the COVID-19 pandemic emergency, research has been oriented toward the development of therapies that could cure critically ill patients and treatments that can reduce the number of hospitalized patients, in order to ease the pressure on health-care systems. Bamlanivimab, developed from human convalescent plasma, was the first monoclonal antibody to become available for emergency use in several countries. Expectations related to its use in COVID-19 patients as a single agent have been largely disregarded, especially against E484K-carrying SARS-CoV-2 variants.Areas covered: In this drug discovery case history, the development of the drug is described starting from the identification and selection of the antibody, from the pre-clinical and clinical trials up to the post-authorization phase.Expert opinion: Bamlanivimab has shown some efficacy in patients with mild to moderate COVID-19. Initially approved as a monotherapy, due to poor efficacy it is currently only usable in combination with etesevimab. Pharmacokinetic limitations and mainly the onset of SARS-CoV-2 variants are the main reasons for this limited clinical use. The use in preventing hospitalization also has ethical limits related to the sustainability of care, especially if, considering similar effectiveness, bamlanivimab is compared with convalescent plasma.

SARS-CoV-2 Variants: A Synopsis of In Vitro Efficacy Data of Convalescent Plasma, Currently Marketed Vaccines, and Monoclonal Antibodies.

We summarize here in vitro evidences of efficacy for convalescent plasma, currently approved vaccines and monoclonal antibodies against SARS-CoV-2 variants of concern (VOC: B.1.1.7, B.1.351, P.1, and B.1.617.2), variants of interest (VOI: B.1.427/B.1.429, P.2, B.1.525, P.3, B.1.526, and B.1.671.1), and other strains (B.1.1.298 and B.1.258delta). While waiting from real world clinical efficacy, these data provide guidance for the treating physician.

The Road towards Polyclonal Anti-SARS-CoV-2 Immunoglobulins (Hyperimmune Serum) for Passive Immunization in COVID-19.

Effective treatments specific for COVID-19 are still lacking. In the setting of passive immunotherapies based on neutralizing antibodies (nAbs), randomized controlled trials of COVID-19 convalescent plasma (CCP) anti-SARS-CoV-2 Spike protein monoclonal antibodies (mAb), which have been granted emergency use authorization, have suggested benefit in early disease course (less than 72 hours from symptoms and seronegative). Meanwhile, polyclonal immunoglobulins (i.e., hyperimmune serum), derived either from CCP donations or from animals immunized with SARS-CoV-2 antigens, are likely to become the next nAb-derived candidate. We here discuss the pros and cons of hyperimmune serum versus CCP and mAb, and summarize the ongoing clinical trials of COVID-19 hyperimmune sera.

Anti-SARS-CoV-2 neutralizing monoclonal antibodies: clinical pipeline.

Monoclonal antibody (mAb) therapy has been previously exploited for viral infections, such as respiratory syncytial virus pneumonia and Ebolavirus disease. In the ongoing COVID-19 pandemic, early signals of efficacy from convalescent plasma therapy have encouraged research and development of anti-SARS-CoV-2 mAbs. While many candidates are in preclinical development, we focus here on anti-SARS-CoV-2 neutralizing mAbs (or mAb cocktails) that represent the late-stage clinical pipeline, i.e., those currently in Phase 2 or Phase 3 clinical trials. We describe the structure, mechanism of action, and ongoing trials for VIR-7831, LY-CoV555, LY-CoV016, BGB-DXP593, REGN-COV2, and CT-P59. We speculate also on the next generation of these mAbs.

Convalescent Plasma Therapy for COVID-19: State of the Art.

Convalescent plasma (CP) therapy has been used since the early 1900s to treat emerging infectious diseases; its efficacy was later associated with the evidence that polyclonal neutralizing antibodies can reduce the duration of viremia. Recent large outbreaks of viral diseases for which effective antivirals or vaccines are still lacking has renewed the interest in CP as a life-saving treatment. The ongoing COVID-19 pandemic has led to the scaling up of CP therapy to unprecedented levels. Compared with historical usage, pathogen reduction technologies have now added an extra layer of safety to the use of CP, and new manufacturing approaches are being explored. This review summarizes historical settings of application, with a focus on betacoronaviruses, and surveys current approaches for donor selection and CP collection, pooling technologies, pathogen inactivation systems, and banking of CP. We additionally list the ongoing registered clinical trials for CP throughout the world and discuss the trial results published thus far.

Exploring pharmacological approaches for managing cytokine storm associated with pneumonia and acute respiratory distress syndrome in COVID-19 patients.

Sars-CoV-2 complications include pneumonia and acute respiratory distress syndrome (ARDS), which require intensive care unit admission. These conditions have rapidly overwhelmed healthcare systems, with detrimental effects on the quality of care and increased mortality. Social isolation strategies have been implemented worldwide with the aim of reducing hospital pressure. Among therapeutic strategies, the use of immunomodulating drugs, to improve prognosis, seems promising. Particularly, since pneumonia and ARDS are associated with a cytokine storm, drugs belonging to therapeutic classes as anti-IL-6, anti-TNF, and JAK inhibitors are currently studied. In this article, we discuss the potential advantages of the most promising pharmacological approaches.