Specifically, ConvP provides hypothesized advantages, including a polyvalent antibody titre approach may provide broader antiviral activity

Specifically, ConvP provides hypothesized advantages, including a polyvalent antibody titre approach may provide broader antiviral activity. variants. Content Weighed against dosing in pet studies, virtually all human trials utilized lower doses significantly. Identifying donors with high virus-neutralizing antibody titres is certainly complicated sufficiently, specifically when new variations get away immunity induced by ancestral variations. Ways to prevent underdosing are (a) usage of ConvP from two different donors, (b) only use ConvP recognized to neutralize the variant with that your patient is contaminated, (c) make use of two ConvP products using a neutralizing antibody titre 1/1250 (when only 1 plasma unit is certainly obtainable, neutralizing antibody titre of 1/2500 is preferred), (d) make use of an antibody check that correlates well with pathogen neutralization (usage of worldwide products per ml (IU/ml) for virus neutralization is strongly encouraged), and (e) use of donors shortly after a third mRNA vaccination may simplify the donor selection Methotrexate (Abitrexate) process. Implications In future trials on ConvP for COVID-19, more stringent donor selection criteria and/or higher volume transfusions should be used. Keywords: Convalescent plasma, COVID-19, Dosing, Pharmacodynamics, Pharmacokinetics, SARS-CoV-2, Therapy, Treatment Introduction Two years into the coronavirus disease 2019 (COVID-19) pandemic, convincing evidence in favour of convalescent plasma (ConvP) as a treatment for COVID-19 is still lacking. Any future role of ConvP for COVID-19 was therefore considered limited, and the most recent WHO guideline formally recommends against the use of ConvP for hospitalized patients, unless in the context of a clinical trial. Several highly potent virus-neutralizing monoclonal antibodies have become a valuable part of our COVID-19 armamentarium, and this seemed to limit any role of ConvP even further. Until recently, newly emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) had a limited impact on the therapeutic value of monoclonal antibodies. Unfortunately, high-level resistance of the Omicron VOC (BA.1) against casirivimab/imdevimab has recently been described by several independent laboratories [1,2]. Almost all other licensed monoclonals seem to be impacted by Methotrexate (Abitrexate) Omicron as well, with sotrovimab as an exception [2]. Furthermore, the BA.2 subvariant of Omicron which is becoming the dominant strain in many countries was recently shown to have a 27-fold lower susceptibility to sotrovimab in one study and Rabbit polyclonal to ADRA1B was not inhibited at all by this drug in another study [[19], [20]]. What nobody had foreseen is that ConvP may become relevant again as a treatment for COVID-19. The effectiveness of virus-neutralizing monoclonal antibodies supports the premise that passive immunotherapy alters the viral pathogenesis; therefore, ConvP will very likely work as long as it is used at the right dose, with the right affinity, in the right patient, and at the right time. Specifically, ConvP has hypothesized advantages, including that a polyvalent antibody titre approach may provide broader antiviral activity. Before we start studying ConvP again, however, we must learn from our recent mistakes. We learned that the risk of underdosing ConvP is high and that a discrepancy between the VOC that infected the donor and recipient can affect efficacy. We also learned that antibody-based therapy works best in patients who are not yet producing virus-neutralizing antibodies. This implies that the window of opportunity is small. In this paper, we focus on the former and try to provide guidance on appropriate dosing of ConvP in future trials or when ConvP is considered for the treatment of immunocompromized patients unable to clear SARS-CoV-2. Methotrexate (Abitrexate) Pharmacokinetics and dynamics in animal studies In a study in rhesus macaques, purified Ig obtained from ConvP with a SARS-CoV-2 50% plaque-reduction neutralizing antibody titre (NAb) of 1/1581 was used to treat COVID-19. Immediately after administration of the Ig at a dose of 250 mg/kg or 25 mg/kg, the NAb titres in the treated animals were 1/511 to 571 and 1/42 to 49, respectively. Both the 250 mg/kg and 25 mg/kg doses were effective at preventing disease, but it became apparent that only the higher dose was effective for treatment. The peak viral load in bronchoalveolar lavage fluid and in the nasopharynx was reduced by 1.84 and 1.26 log, respectively, with the 250 mg/kg dose, but the viral load reduction after the 25 mg/kg dose was much more limited (0.64 log) in Methotrexate (Abitrexate) the bronchoalveolar lavage fluid and completely absent in the nasopharynx [3]. The study in macaques may provide a framework for.