Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, continues to strain healthcare systems. While dexamethasone has shown a significant reduction in mortality in hospitalized patients requiring supplemental oxygen or ICU admission, the role of direct antiviral therapy remains less established. The efficacy of repurposed antiviral drugs has been limited, highlighting an unmet need for effective and readily available antiviral treatments. SARS-CoV-2-neutralizing antibodies are a promising therapeutic avenue, with potent monoclonal antibodies under investigation. Convalescent plasma (ConvP), containing high levels of SARS-CoV-2-neutralizing antibodies, offers a potentially scalable alternative. These antibodies reduce viral infectivity by binding to the viral surface and blocking replication. They primarily target the receptor-binding domain (RBD) of the Spike protein, preventing SARS-CoV-2 attachment to epithelial cells. ConvP has shown some success in previous SARS and MERS outbreaks, and preclinical research suggests its protective effect in hamsters. However, conclusive evidence of ConvP's effectiveness in human SARS-CoV-2 infection remains limited, with studies yielding mixed results and meta-analyses suggesting benefit only in specific patient subsets. The lack of conclusive evidence led to this study, which aimed to evaluate the efficacy of ConvP in hospitalized COVID-19 patients by assessing its impact on clinical symptoms, SARS-CoV-2 shedding, and inflammatory markers.

Several studies have explored the use of convalescent plasma in treating severe acute respiratory infections caused by viruses, including SARS-CoV and MERS-CoV. Some small studies reported some success, while others showed mixed or negative results. Meta-analyses have attempted to synthesize the evidence, but the results are inconsistent, with some suggesting benefit only for certain patient subgroups. Preclinical research, specifically in animal models, has provided some evidence supporting the potential of convalescent plasma to reduce disease severity. However, the lack of robust clinical trial data on the efficacy of convalescent plasma in COVID-19 patients has led to ongoing debates and the need for further research.

This study was a multicenter, open-label, randomized clinical trial conducted in 14 Dutch hospitals. The study enrolled 86 hospitalized patients with laboratory-confirmed SARS-CoV-2 infection. Patients were randomized 1:1 to receive either standard of care (SoC) or SoC plus 300 mL of ConvP with high titers of neutralizing antibodies. The primary endpoint was overall mortality at 60 days post-enrollment. Secondary endpoints included improvement in WHO COVID-19 disease severity score, hospital length of stay, SARS-CoV-2 viral shedding, humoral immunity, and inflammation. Detailed baseline characteristics were collected, including demographics, comorbidities, and disease severity. Blood samples were collected for immunological analyses (including ELISA and PRNT50 assays to measure antibody levels and neutralization capacity) and nasopharyngeal swabs for virological analyses (RT-PCR and viral culture). Serum cytokines were also measured to assess the inflammatory response. Statistical analyses included logistic regression, proportional hazards models (accounting for competing risks), mixed-effects models, and other appropriate methods.

The study found no significant overall clinical benefit from ConvP treatment in hospitalized COVID-19 patients. There was no difference in mortality, time to improvement on the WHO disease severity scale, hospital length of stay, or viral clearance between the ConvP and SoC groups. Immunological analyses revealed that the majority (80%) of patients already possessed potent neutralizing antibodies at hospital admission, with titers comparable to those in the selected ConvP donors. Furthermore, ConvP treatment did not significantly affect inflammatory cytokine levels. The high prevalence of pre-existing neutralizing antibodies in hospitalized patients likely contributed to the lack of observed clinical benefit from ConvP treatment. The trial was prematurely terminated due to the low likelihood of detecting a significant clinical effect given the high baseline antibody levels in the patient population. No serious adverse events related to ConvP were observed.

This study's findings challenge the assumption that ConvP would benefit hospitalized COVID-19 patients. The lack of observed benefit highlights the importance of considering the timing of intervention and the baseline immune status of patients. The high prevalence of pre-existing neutralizing antibodies in hospitalized patients suggests that ConvP administration might be more beneficial earlier in the disease course, before the development of a robust autologous humoral immune response. The results underscore the critical need for accurate selection criteria for ConvP treatment and optimal timing of intervention. Future studies should focus on earlier stages of infection, ideally before the patient's own immune system mounts a significant antibody response, to maximize the potential benefits of ConvP treatment.

This randomized controlled trial demonstrated no clinical benefit from convalescent plasma in hospitalized COVID-19 patients. The high prevalence of pre-existing neutralizing antibodies in this population likely explains this result. Future research should explore the use of convalescent plasma much earlier in the disease course, ideally before the development of a substantial autologous antibody response. Rigorous selection of patients and donors, including functional antibody assays, is crucial for future trials.

The early termination of the trial limits the definitive conclusions that can be drawn. The study's focus on hospitalized patients, who already had some degree of immune response, might not fully reflect the potential benefits of convalescent plasma in earlier stages of the disease. The study's sample size may have been insufficient to detect smaller but potentially clinically relevant effects of ConvP treatment. The lack of information on corticosteroid use could be a confounding factor.