Focosi, Daniele

ABSTRACT Anti‐Spike monoclonal antibodies (mAbs) progressively lost efficacy during the COVID‐19 pandemic due to the emergence and predominance of resistant SARS‐CoV‐2 variants. By contrast, high‐titre COVID‐19 convalescent plasma (CCP) collected from vaccinated donors recently recovered from infection provides a polyclonal source of antibodies that remains effective in clearing SARS‐CoV‐2 in immunosuppressed patients, unable to mount an adequate immune response against the virus. We conducted a systematic review and individual participant data meta‐analysis to examine the effect of CCP in immunocompromised patients persistently positive for SARS‐CoV‐2 viraemia following mAb therapy, and to evaluate possible biological factors associated with a favourable outcome. Electronic databases were searched for studies published from January 2020 to January 2026. All studies including eligible cases were considered in the systematic review. Unpublished cases were also collected from investigators of the selected studies. The protocol was registered at PROSPERO (CRD420251142891). Forty‐seven cases (30 cases from 12 published studies and 17 unpublished cases) were included. In 33 out of 47 patients (70.2%) with a mAb‐resistant infection, SARS‐CoV‐2 clearance occurred following CCP transfusion, with a mean of 2.7 CCP units administered. In logistic regression, total CCP volume transfused was positively associated with SARS‐CoV‐2 clearance. In conclusion, CCP transfusion was associated with SARS‐CoV‐2 clearance in persistently positive immunocompromised patients following failure of anti‐Spike mAb therapy.

SUMMARY COVID-19 convalescent plasma (CCP) was the first specific therapy deployed for treating SARS-CoV-2 infection. CCP was successfully deployed in both resource-poor and resource-rich countries, establishing that convalescent plasma (CP) is a feasible option for combating the next pandemic. CCP reduced mortality and progression to hospitalization when used early in the disease with high-titer units. This knowledge was gained from a worldwide effort that included more than 50 countries. However, the deployment of CCP was haphazard and varied among countries. Clinical studies suffered from a lack of standardization regarding study design, CCP antibody dosing, timing of administration, and participant disease severity. Unfortunately, the hard-won knowledge from the serum therapy era in the early 20th century, which indicated that effective antibody therapy requires early use in the disease with a sufficient antibody dose, was largely forgotten. Many studies tested CCP late in the disease or without sufficient antibody titer and thus reported negative findings. Trial heterogeneity made it difficult to combine the results of studies. However, despite tremendous heterogeneity in study design and participant populations, meta-analysis revealed strong signals of efficacy when given early with high antiviral-specific antibody levels. When the next pandemic occurs, humanity is likely to resort to CP again. To avoid another chaotic rollout, planning for CP use should begin well before that emergency arrives and must involve both physician education on the principles of antibody therapy and clinical trial designs that test its efficacy in optimal conditions, which include early use with sufficient antibody doses.

AbstractInfluenzavirus is among the most relevant candidates for a next pandemic. We review here the phylogeny of former influenza pandemics, and discuss candidate lineages. After briefly reviewing the other existing antiviral options, we discuss in detail the evidences supporting the efficacy of passive immunotherapies against influenzavirus, with a focus on convalescent plasma.

Plasma collected from people recovered from COVID-19 (COVID-19 convalescent plasma, CCP) was the first antibody-based therapy employed to fight the pandemic. CCP was, however, often employed in combination with other drugs, such as the antiviral remdesivir and glucocorticoids. The possible effect of such interaction has never been investigated systematically. To assess the safety and efficacy of CCP combined with other agents for treatment of patients hospitalized for COVID-19, a systematic literature search using appropriate Medical Subject Heading (MeSH) terms was performed through PubMed, EMBASE, Cochrane central, medRxiv and bioRxiv. The main outcomes considered were mortality and safety of CCP combined with other treatments versus CCP alone. This review was carried out in accordance with Cochrane methodology including risk of bias assessment and grading of the quality of evidence. Measure of treatment effect was the risk ratio (RR) together with 95% confidence intervals (CIs). A total of 11 studies (8 randomized controlled trials [RCTs] and 3 observational) were included in the systematic review, 4 studies with CCP combined with remdesivir and 6 studies with CCP combined with corticosteroids, all involving hospitalized patients. One RCT reported information on both remdesivir and steroids use with CCP. The use of CCP combined with remdesivir was associated with a significantly reduced risk of death (RR 0.74; 95% CI 0.56–0.97; p = 0.03; moderate certainty of evidence), while the use of steroids with CCP did not modify the mortality risk (RR 0.72; 95% CI 0.34–1.51; p = 0.38; very low certainty of evidence). Not enough safety data were retrieved form the systematic literature analysis. The current evidence from the literature suggests a potential beneficial effect on mortality of combined CCP plus remdesivir compared to CCP alone in hospitalized COVID-19 patients. No significant clinical interaction was found between CCP and steroids.

Recent 2022 SARS-CoV-2 Omicron variants, have acquired resistance to most neutralizing anti-Spike monoclonal antibodies authorized, and the BQ.1.* sublineages are notably resistant to all authorized monoclonal antibodies. Polyclonal antibodies from individuals both vaccinated and recently recovered from Omicron COVID-19 (VaxCCP) could retain new Omicron neutralizing activity. Here we reviewed BQ.1.* virus neutralization data from 920 individual patient samples from 43 separate cohorts defined by boosted vaccinations (Vax) with or without recent Omicron COVID-19, as well as infection without vaccination (CCP) to determine level of BQ.1.* neutralizing antibodies and percent of plasma samples with neutralizing activity. More than 90 % of the plasma samples from individuals in the recently (within 6 months) boosted VaxCCP study cohorts neutralized BQ.1.1, and BF.7 with 100 % neutralization of WA-1, BA.4/5, BA.4.6 and BA.2.75. The geometric mean of the geometric mean 50 % neutralizing titres (GM (GMT 50 ) were 314, 78 and 204 for BQ.1.1, XBB.1 and BF.7, respectively. Compared to VaxCCP, plasma sampled from COVID-19 naïve subjects who also recently (within 6 months) received at least a third vaccine dose had about half of the GM (GMT 50 ) for all viral variants. Boosted VaxCCP characterized by either recent vaccine dose or infection event within 6 months represents a robust, variant-resilient, neutralizing antibody source against the new Omicron BQ.1.1, XBB.1 and BF.7 variants.